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1. EG-VEGF maternal levels predict spontaneous preterm birth in the second and third trimesters in pregnant women with risk factors for placenta-mediated complications

Author: Tiphaine Raia-Barjat, Céline Chauleur, Constance Collet, Florence Rancon, Pascale Hoffmann, Morgane Desseux, Nicolas Lemaitre, Mohamed Benharouga, Antoine Giraud, and Nadia Alfaidy
Subjects: Medicine, Science
Abstract: Abstract Prediction of spontaneous preterm birth in asymptomatic women remains a great challenge for the public health system. The aim of the study was to determine the informational value of EG-VEGF circulating levels for prediction of spontaneous preterm birth in the second and third trimesters in pregnant women at high risk for placenta-mediated complications. A prospective multicenter cohort study including 200 pregnant patients with five-serum sampling per patient. Women with spontaneous preterm birth have higher concentrations of serum EG-VEGF than uncomplicated patients at 24 weeks, 28 weeks and 32 weeks (p = 0.03, 0.02 and
Published: 2023
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2. The Multifaceted Functions of Prion Protein (PrPC) in Cancer

Author: Roland Abi Nahed, Hasan Safwan-Zaiter, Kevin Gemy, Camille Lyko, Mélanie Boudaud, Morgane Desseux, Christel Marquette, Tiphaine Barjat, Nadia Alfaidy, and Mohamed Benharouga
Subjects: prion protein (PrPC), cancer, drug resistance, therapeutic target, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: The cellular prion protein (PrPC) is a glycoprotein anchored to the cell surface by glycosylphosphatidylinositol (GPI). PrPC is expressed both in the brain and in peripheral tissues. Investigations on PrPC’s functions revealed its direct involvement in neurodegenerative and prion diseases, as well as in various physiological processes such as anti-oxidative functions, copper homeostasis, trans-membrane signaling, and cell adhesion. Recent findings have revealed the ectopic expression of PrPC in various cancers including gastric, melanoma, breast, colorectal, pancreatic, as well as rare cancers, where PrPC promotes cellular migration and invasion, tumor growth, and metastasis. Through its downstream signaling, PrPC has also been reported to be involved in resistance to chemotherapy and tumor cell apoptosis. This review summarizes the variance of expression of PrPC in different types of cancers and discusses its roles in their development and progression, as well as its use as a potential target to treat such cancers.
Published: 2023
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3. Effects of Prokineticins on Cerebral Cell Function and Blood–Brain Barrier Permeability

Author: Hadi Younes, Ioanna Kyritsi, Zineb Mahrougui, Mohamed Benharouga, Nadia Alfaidy, and Christel Marquette
Subjects: prokineticin, prokineticin receptor, receptors antagonists, blood–brain barrier integrity, brain endothelial cells, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract: Prokineticins are a family of small proteins with diverse roles in various tissues, including the brain. However, their specific effects on different cerebral cell types and blood–brain barrier (BBB) function remain unclear. The aim of this study was to investigate the effects of PROK1 and PROK2 on murine cerebral cell lines, bEnd.3, C8.D30, and N2a, corresponding to microvascular endothelial cells, astrocytes and neurons, respectively, and on an established BBB co-culture model. Western blot analysis showed that prokineticin receptors (PROKR1 and PROKR2) were differentially expressed in the considered cell lines. The effect of PROK1 and PROK2 on cell proliferation and migration were assessed using time-lapse microscopy. PROK1 decreased neural cells’ proliferation, while it had no effect on the proliferation of endothelial cells and astrocytes. In contrast, PROK2 reduced the proliferation of all cell lines tested. Both PROK1 and PROK2 increased the migration of all cell lines. Blocking PROKRs with the PROKR1 antagonist (PC7) and the PROKR2 antagonist (PKR-A) inhibited astrocyte PROK2-mediated migration. Using the insert co-culture model of BBB, we demonstrated that PROKs increased BBB permeability, which could be prevented by PROKRs’ antagonists.
Published: 2023
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4. NLRP7 Enhances Choriocarcinoma Cell Survival and Camouflage in an Inflammasome Independent Pathway

Author: Déborah Reynaud, Nadia Alfaidy, Constance Collet, Nicolas Lemaitre, Frederic Sergent, Céline Miege, Emmanuelle Soleilhac, Alaa Al Assi, Padma Murthi, Gilles Courtois, Marie-Odile Fauvarque, Rima Slim, Mohamed Benharouga, and Roland Abi Nahed
Subjects: NLRP7, inflammasome, gestational choriocarcinoma, camouflage, NF-κB, cancer, Cytology, QH573-671
Abstract: Background: Gestational choriocarcinoma (GC) is a highly malignant trophoblastic tumor that often develops from a complete hydatidiform mole (HM). NLRP7 is the major gene responsible for recurrent HM and is involved in the innate immune response, inflammation and apoptosis. NLRP7 can function in an inflammasome-dependent or -independent pathway. Recently, we have demonstrated that NLRP7 is highly expressed in GC tumor cells and contributes to their tumorigenesis. However, the underlying mechanisms are still unknown. Here, we investigated the mechanism by which NLRP7 controls these processes in malignant (JEG-3) and non-tumor (HTR8/SVneo) trophoblastic cells. Cell survival, dedifferentiation, camouflage, and aggressiveness were compared between normal JEG-3 cells or knockdown for NLRP7, JEG-3 Sh NLRP7. In addition, HTR8/SVneo cells overexpressing NLRP7 were used to determine the impact of NLRP7 overexpression on non-tumor cells. NLRP7 involvement in tumor cell growth and tolerance was further characterized in vivo using the metastatic mouse model of GC. Results: We demonstrate that NLRP7 (i) functions in an inflammasome-dependent and -independent manners in HTR8/SVneo and JEG-3 cells, respectively; (ii) differentially regulates the activity of NF-κB in tumor and non-tumor cells; (iii) increases malignant cell survival, dedifferentiation, and camouflage; and (iv) facilitates tumor cells colonization of the lungs in the preclinical model of GC. Conclusions: This study demonstrates for the first time the mechanism by which NLRP7, independently of its inflammasome machinery, contributes to GC growth and tumorigenesis. The clinical relevance of NLRP7 in this rare cancer highlights its potential therapeutic promise as a molecular target to treat resistant GC patients.
Published: 2023
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5. The Emerging Role of the Prokineticins and Homeobox Genes in the Vascularization of the Placenta: Physiological and Pathological Aspects

Author: Nadia Alfaidy, Sophie Brouillet, Gayathri Rajaraman, Bill Kalionis, Pascale Hoffmann, Tiphaine Barjat, Mohamed Benharouga, and Padma Murthi
Subjects: vessel development, endothelial cells, angiogenesis, prokineticins, homeobox genes, vascularization, Physiology, QP1-981
Abstract: Vasculogenesis and angiogenesis are key processes of placental development, which occur throughout pregnancy. Placental vasculogenesis occurs during the first trimester of pregnancy culminating in the formation of hemangioblasts from intra-villous stem cells. Placental angiogenesis occurs subsequently, forming new blood vessels from existing ones. Angiogenesis also takes place at the fetomaternal interface, allowing essential spiral arteriole remodeling to establish the fetomaternal circulation. Vasculogenesis and angiogenesis in animal models and in humans have been studied in a wide variety of in vitro, physiological and pathological conditions, with a focus on the pro- and anti-angiogenic factors that control these processes. Recent studies revealed roles for new families of proteins, including direct participants such as the prokineticin family, and regulators of these processes such as the homeobox genes. This review summarizes recent advances in understanding the molecular mechanisms of actions of these families of proteins. Over the past decade, evidence suggests increased production of placental anti-angiogenic factors, as well as angiogenic factors are associated with fetal growth restriction (FGR) and preeclampsia (PE): the most threatening pathologies of human pregnancy with systemic vascular dysfunction. This review also reports novel clinical strategies targeting members of these family of proteins to treat PE and its consequent effects on the maternal vascular system.
Published: 2020
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6. Animal Models of Chorioamnionitis: Considerations for Translational Medicine

Author: Tiphaine Raia-Barjat, Margaux Digonnet, Antoine Giraud, Taghreed Ayash, Seline Vancolen, Mohamed Benharouga, Céline Chauleur, Nadia Alfaidy, and Guillaume Sébire
Subjects: animal models, chorioamnionitis, preterm birth, Biology (General), QH301-705.5
Abstract: Preterm birth is defined as any birth occurring before 37 completed weeks of gestation by the World Health Organization. Preterm birth is responsible for perinatal mortality and long-term neurological morbidity. Acute chorioamnionitis is observed in 70% of premature labor and is associated with a heavy burden of multiorgan morbidities in the offspring. Unfortunately, chorioamnionitis is still missing effective biomarkers and early placento- as well as feto-protective and curative treatments. This review summarizes recent advances in the understanding of the underlying mechanisms of chorioamnionitis and subsequent impacts on the pregnancy outcome, both during and beyond gestation. This review also describes relevant and current animal models of chorioamnionitis used to decipher associated mechanisms and develop much needed therapies. Improved knowledge of the pathophysiological mechanisms underpinning chorioamnionitis based on preclinical models is a mandatory step to identify early in utero diagnostic biomarkers and design novel anti-inflammatory interventions to improve both maternal and fetal outcomes.
Published: 2022
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7. Role of NLRP7 in Normal and Malignant Trophoblast Cells

Author: Roland Abi Nahed, Maya Elkhoury Mikhael, Deborah Reynaud, Constance Collet, Nicolas Lemaitre, Thierry Michy, Pascale Hoffmann, Frederic Sergent, Christel Marquette, Padma Murthi, Tiphaine Raia-Barjat, Nadia Alfaidy, and Mohamed Benharouga
Subjects: NLRP7, inflammasome, choriocarcinoma, pregnancy, maternal immune tolerance, tumor microenvironment, Biology (General), QH301-705.5
Abstract: Gestational choriocarcinoma (CC) is an aggressive cancer that develops upon the occurrence of abnormal pregnancies such as Hydatidiform moles (HMs) or upon non-molar pregnancies. CC cells often metastasize in multiple organs and can cause maternal death. Recent studies have established an association between recurrent HMs and mutations in the Nlrp7 gene. NLRP7 is a member of a new family of proteins that contributes to innate immune processes. Depending on its level of expression, NLRP7 can function in an inflammasome-dependent or independent pathway. To date, the role of NLRP7 in normal and in malignant human placentation remains to be elucidated. We have recently demonstrated that NLRP7 is overexpressed in CC trophoblast cells and may contribute to their acquisition of immune tolerance via the regulation of key immune tolerance-associated factors, namely HLA family, βCG and PD-L1. We have also demonstrated that NLRP7 increases trophoblast proliferation and decreases their differentiation, both in normal and tumor conditions. Actual findings suggest that NLRP7 expression may ensure a strong tolerance of the trophoblast by the maternal immune system during normal pregnancy and may directly affect the behavior and aggressiveness of malignant trophoblast cells. The proposed review summarizes recent advances in the understanding of the significance of NLRP7 overexpression in CC and discusses its multifaceted roles, including its function in an inflammasome-dependent or independent pathways.
Published: 2022
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8. NLRP7 Promotes Choriocarcinoma Growth and Progression through the Establishment of an Immunosuppressive Microenvironment

Author: Deborah Reynaud, Roland Abi Nahed, Nicolas Lemaitre, Pierre-Adrien Bolze, Wael Traboulsi, Frederic Sergent, Christophe Battail, Odile Filhol, Vincent Sapin, Houssine Boufettal, Pascale Hoffmann, Touria Aboussaouira, Padma Murthi, Rima Slim, Mohamed Benharouga, and Nadia Alfaidy
Subjects: choriocarcinoma, hydatidiform mole, NLRP7, tumor microenvironment, maternal immune tolerance, orthotopic model of choriocarcinoma, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: The inflammatory gene NLRP7 is the major gene responsible for recurrent complete hydatidiform moles (CHM), an abnormal pregnancy that can develop into gestational choriocarcinoma (CC). However, the role of NLRP7 in the development and immune tolerance of CC has not been investigated. Three approaches were employed to define the role of NLRP7 in CC development: (i) a clinical study that analyzed human placenta and sera collected from women with normal pregnancies, CHM or CC; (ii) an in vitro study that investigated the impact of NLRP7 knockdown on tumor growth and organization; and (iii) an in vivo study that used two CC mouse models, including an orthotopic model. NLRP7 and circulating inflammatory cytokines were upregulated in tumor cells and in CHM and CC. In tumor cells, NLRP7 functions in an inflammasome-independent manner and promoted their proliferation and 3D organization. Gravid mice placentas injected with CC cells invalidated for NLRP7, exhibited higher maternal immune response, developed smaller tumors, and displayed less metastases. Our data characterized the critical role of NLRP7 in CC and provided evidence of its contribution to the development of an immunosuppressive maternal microenvironment that not only downregulates the maternal immune response but also fosters the growth and progression of CC.
Published: 2021
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9. Risk factors and poor prognostic factors of preeclampsia in Ibn Rochd University Hospital of Casablanca: about 401 preeclamptic cases

Author: Meriem Benfateh, Souadou Cissoko, Houssine Boufettal, Jean-Jacques Feige, Naima Samouh, Touria Aboussaouira, Mohamed Benharouga, and Nadia Alfaidy
Subjects: preeclampsia, risk factors, maternal prognostic, fetal prognostic, Medicine
Abstract: Preeclampsia is a gestational pathology that complicates 2 to 8% of pregnancies and is one of the major causes of maternal and fetal morbidity and mortality worldwide. The aim of this work was to study the epidemiological profile of preeclampsia in Casablanca and to identify risk factors as well as factors of poor maternal and fetal prognosis. 401 preeclamptic cases were collected in the gynecology-obstetrics "C" Service of Lalla Meryem Maternity of Ibn Rochd University Hospital of Casablanca (2010-2011) were included in this study and a statistical analysis with the SPSS software version (16.0) was performed. We used the Chi-2 test to analyze qualitatives variables and Student's test and ANOVA (analysis of variance) for quantitative variables. The incidence of preeclampsia was (7.1%). The epidemiological profile was that of a primipara (57.6%), average age 30 years and (66.8%) of pregnancies were not followed. Multiparity was a factor of poor maternal prognosis (p = 0.007). The low gestational age and no prenatal care were factors of poor prognosis maternal as well as fetal. Risk factors frequently found in our patients were obesity (15.21%) and chronic hypertension (5.73%) as vascular-renal history; abortion (16.46%) and perinatal death (5.24%) as obstetric history. Pre-eclampsia is a common obstetric pathology in our context. Better prenatal care and early diagnosis could reduce its incidence.
Published: 2018
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10. Evidence-Based View of Safety and Effectiveness of Prokineticin Receptors Antagonists during Pregnancy

Author: Deborah Reynaud, Frederic Sergent, Roland Abi Nahed, Wael Traboulsi, Constance Collet, Christel Marquette, Pascale Hoffmann, Gianfranco Balboni, Qun-Yong Zhou, Padma Murthi, Mohamed Benharouga, and Nadia Alfaidy
Subjects: prokineticin antagonists, EG-VEGF, pregnancy pathologies, therapy, angiogenesis, trophoblast invasion, Biology (General), QH301-705.5
Abstract: Endocrine gland derived vascular endothelial growth factor (EG-VEGF) is a canonical member of the prokineticin (PROKs) family. It acts via the two G-protein coupled receptors, namely PROKR1 and PROKR2. We have recently demonstrated that EG-VEGF is highly expressed in the human placenta; contributes to placental vascularization and growth and that its aberrant expression is associated with pregnancy pathologies including preeclampsia and fetal growth restriction. These findings strongly suggested that antagonization of its receptors may constitute a potential therapy for the pregnancy pathologies. Two specific antagonists of PROKR1 (PC7) and for PROKR2 (PKRA) were reported to reverse PROKs adverse effects in other systems. In the view of using these antagonists to treat pregnancy pathologies, a proof of concept study was designed to determine the biological significances of PC7 and PKRA in normal pregnancy outcome. PC7 and PKRA were tested independently or in combination in trophoblast cells and during early gestation in the gravid mouse. Both independent and combined treatments uncovered endogenous functions of EG-VEGF. The independent use of antagonists distinctively identified PROKR1 and PROKR2-mediated EG-VEGF signaling on trophoblast differentiation and invasion; thereby enhancing feto-placental growth and pregnancy outcome. Thus, our study provides evidence for the potential safe use of PC7 or PKRA to improve pregnancy outcome.
Published: 2021
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11. Copper-Associated Oxidative Stress Contributes to Cellular Inflammatory Responses in Cystic Fibrosis

Author: Amal Kouadri, Johanna Cormenier, Kevin Gemy, Laurence Macari, Peggy Charbonnier, Pierre Richaud, Isabelle Michaud-Soret, Nadia Alfaidy, and Mohamed Benharouga
Subjects: inflammation, cystic fibrosis, oxidative stress, CFTR, copper, lung, Biology (General), QH301-705.5
Abstract: Cystic fibrosis (CF) is caused by mutations in the gene encoding the CF Transmembrane Conductance Regulator (CFTR), an apical chloride channel. An early inflammation (EI) in the lung of CF patients occurring in the absence of any bacterial infection has been reported. This EI has been proposed to be associated with oxidative stress (OX-S), generated by deregulations of the oxidant/antioxidant status. Recently, we demonstrated that copper (Cu), an essential trace element, mediates OX-S in bronchial cells. However, the role of this element in the development of CF-EI, in association with OX-S, has never been investigated. Using healthy (16HBE14o-; HBE), CF (CFBE14o-; CFBE), and corrected-wild type CFTR CF (CFBE-wt) bronchial cells, we characterized the inflammation and OX-S profiles in relation to the copper status and CFTR expression and function. We demonstrated that CFBE cells exhibited a CFTR-independent intrinsic inflammation. These cells also exhibited an alteration in mitochondria, UPR (Unfolded Protein Response), catalase, Cu/Zn- and Mn-SOD activities, and an increase in the intracellular content of iron, zinc, and Cu. The increase in Cu concentration was associated with OX-S and inflammatory responses. These data identify cellular Cu as a key factor in the generation of CF-associated OX-S and opens new areas of investigation to better understand CF-associated EI.
Published: 2021
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12. EG-VEGF Maternal levels predict spontaneous preterm birth in the second and third trimesters of pregnancy

Author: Tiphaine Raia-Barjat, Céline CHAULEUR, Constance Collet, Florence Rancon, Pascale Hoffmann, Morgane Desseux, Nicolas Lemaitre, Mohamed Benharouga, Antoine Giraud, and Nadia Alfaidy
Abstract: Background: Prediction of spontaneous preterm birth in asymptomatic women remains a great challenge for the public health system. The aim of the study was to determine the informational value of EG-VEGF circulating levels in pregnant women at high risk for prediction of spontaneous preterm birth in the second and third trimesters. Methods: A prospective multicenter cohort study including 200 pregnant patients with five-serum sampling per patient. Results: Women with spontaneous preterm birth have higher concentrations of serum EG-VEGF than uncomplicated patients at 24 weeks, 28 weeks and 32 weeks (p= 0.03, 0.02 and Conclusions: Serum EG-VEGF concentrations could be considered as a reliable biomarker of spontaneous preterm birth in high-risk pregnant women.
Published: 2023

13. All suupplemental figures clean from Antagonism of EG-VEGF Receptors as Targeted Therapy for Choriocarcinoma Progression In Vitro and In Vivo

Author: Nadia Alfaidy, Mohamed Benharouga, Jean J. Feige, Touria Aboussaouira, François Mallet, Philippe Sauthier, Aude Salomon, Pierre A. Bolze, Valentina Onnis, Gianfranco Balboni, Qun Y. Zhou, Mohammed Benlahfid, Pascale Hoffmann, Rima Slim, Sophie Brouillet, Houssine Boufettal, Frédéric Sergent, and Wael Traboulsi
Abstract: Supplemental Methods Figure S1: Reports clinical information's about normal pregnant women, patients with complete hydatiform moles or choriocarcinoma. Figure S2: Experimental procedure. Figure S3: Quantification of EG-VEGF PROKR1 and PROKR2 protein expression in CTL, Complete hydatiform mole (CHM) and choriocarcinoma (CC) placental section. Figure S4: EG-VEGF effect on JEG3 migration, in the absence or presence of PROKR1 or PROKR2 antagonists. Figure S5: JEG3-luc injected mice exhibited arrested gestation and disorganized vascularization. Figure S6: Antibody microarray analysis. Figure S7: Characterization of the angiogenic status of sera and placentas collected from CTL, CHM and CC patients. Figure S8: Antibody angiogenic microarray analysis of sera collected from CTL, CHM and CC patients.
Published: 2023

14. Data from Antagonism of EG-VEGF Receptors as Targeted Therapy for Choriocarcinoma Progression In Vitro and In Vivo

Author: Nadia Alfaidy, Mohamed Benharouga, Jean J. Feige, Touria Aboussaouira, François Mallet, Philippe Sauthier, Aude Salomon, Pierre A. Bolze, Valentina Onnis, Gianfranco Balboni, Qun Y. Zhou, Mohammed Benlahfid, Pascale Hoffmann, Rima Slim, Sophie Brouillet, Houssine Boufettal, Frédéric Sergent, and Wael Traboulsi
Abstract: Purpose: Choriocarcinoma (CC) is the most malignant gestational trophoblastic disease that often develops from complete hydatidiform moles (CHM). Neither the mechanism of CC development nor its progression is yet characterized. We recently identified endocrine gland–derived vascular endothelial growth factor (EG-VEGF) as a novel key placental growth factor that controls trophoblast proliferation and invasion. EG-VEGF acts via two receptors, PROKR1 and PROKR2. Here, we demonstrate that EG-VEGF receptors can be targeted for CC therapy.Experimental Design: Three approaches were used: (i) a clinical investigation comparing circulating EG-VEGF in control (n = 20) and in distinctive CHM (n = 38) and CC (n = 9) cohorts, (ii) an in vitro study investigating EG-VEGF effects on the CC cell line JEG3, and (iii) an in vivo study including the development of a novel CC mouse model, through a direct injection of JEG3-luciferase into the placenta of gravid SCID-mice.Results: Both placental and circulating EG-VEGF levels were increased in CHM and CC (×5) patients. EG-VEGF increased JEG3 proliferation, migration, and invasion in two-dimensional (2D) and three-dimensional (3D) culture systems. JEG3 injection in the placenta caused CC development with large metastases compared with their injection into the uterine horn. Treatment of the animal model with EG-VEGF receptor's antagonists significantly reduced tumor development and progression and preserved pregnancy. Antibody-array and immunohistological analyses further deciphered the mechanism of the antagonist's actions.Conclusions: Our work describes a novel preclinical animal model of CC and presents evidence that EG-VEGF receptors can be targeted for CC therapy. This may provide safe and less toxic therapeutic options compared with the currently used multi-agent chemotherapies. Clin Cancer Res; 23(22); 7130–40. ©2017 AACR.
Published: 2023

15. Role of NLRP7 in Normal and Malignant Trophoblast Cells

Author: Roland Abi Nahed, Maya Elkhoury Mikhael, Deborah Reynaud, Constance Collet, Nicolas Lemaitre, Thierry Michy, Pascale Hoffmann, Frederic Sergent, Christel Marquette, Padma Murthi, Tiphaine Raia-Barjat, Nadia Alfaidy, Mohamed Benharouga, Mécanisme de l’Angiogenèseet des BarrièresBiologiques (MAB2), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), and ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017)
Subjects: Medicine (miscellaneous), General Biochemistry, Genetics and Molecular Biology, [SDV.BDLR.RS]Life Sciences [q-bio]/Reproductive Biology/Sexual reproduction
Abstract: International audience; Gestational choriocarcinoma (CC) is an aggressive cancer that develops upon the occurrence of abnormal pregnancies such as Hydatidiform moles (HMs) or upon non-molar pregnancies. CC cells often metastasize in multiple organs and can cause maternal death. Recent studies have established an association between recurrent HMs and mutations in the Nlrp7 gene. NLRP7 is a member of a new family of proteins that contributes to innate immune processes. Depending on its level of expression, NLRP7 can function in an inflammasome-dependent or independent pathway. To date, the role of NLRP7 in normal and in malignant human placentation remains to be elucidated. We have recently demonstrated that NLRP7 is overexpressed in CC trophoblast cells and may contribute to their acquisition of immune tolerance via the regulation of key immune tolerance-associated factors, namely HLA family, βCG and PD-L1. We have also demonstrated that NLRP7 increases trophoblast proliferation and decreases their differentiation, both in normal and tumor conditions. Actual findings suggest that NLRP7 expression may ensure a strong tolerance of the trophoblast by the maternal immune system during normal pregnancy and may directly affect the behavior and aggressiveness of malignant trophoblast cells. The proposed review summarizes recent advances in the understanding of the significance of NLRP7 overexpression in CC and discusses its multifaceted roles, including its function in an inflammasome-dependent or independent pathways.
Published: 2021

16. Significance of the placental barrier in antenatal viral infections

Author: Hannah E.J. Yong, Gayathri Rajaraman, Padma Murthi, Shiao-Yng Chan, Frantisek Staud, Amlan Chakraborty, Nadia Alfaidy, Sharon D. Ricardo, Mohamed Benharouga, Université Grenoble Alpes, Inserm, CEA, BIG-Biologie du Cancer et de l’Infection, Grenoble, France, Mécanisme de l’Angiogenèseet des BarrièresBiologiques (MAB2), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)
Subjects: Offspring, viruses, Placenta, HIV Infections, Zika virus, [SDV.BDLR.RS]Life Sciences [q-bio]/Reproductive Biology/Sexual reproduction, Barrier function, 03 medical and health sciences, 0302 clinical medicine, Syncytiotrophoblast, Immune system, Fetus, Pregnancy, Medicine, Humans, Severe acute respiratory syndrome coronavirus 2, Pregnancy Complications, Infectious, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Viral infections, biology, business.industry, Transmission (medicine), SARS-CoV-2, Zika Virus Infection, Human immunodeficiency virus, Immune cells, COVID-19, Zika Virus, medicine.disease, biology.organism_classification, Infectious Disease Transmission, Vertical, 3. Good health, medicine.anatomical_structure, Virus Diseases, 030220 oncology & carcinogenesis, embryonic structures, Immunology, HIV-1, Molecular Medicine, Female, business
Abstract: The placenta provides a significant physical and physiological barrier to prevent fetal infection during pregnancy. Nevertheless, it is at times breached by pathogens and leads to vertical transmission of infection from mother to fetus. This review will focus specifically on the Zika flavivirus, the HIV retrovirus and the emerging SARS-CoV2 coronavirus, which have affected pregnant women and their offspring in recent epidemics. In particular, we will address how viral infections affect the immune response at the maternal-fetal interface and how the placental barrier is physically breached and discuss the consequences of infection on various aspects of placental function to support fetal growth and development. Improved understanding of how the placenta responds to viral infections will lay the foundation for developing therapeutics to these and emergent viruses, to minimise the harms of infection to the offspring.
Published: 2021

17. NLRP7 Promotes Choriocarcinoma Growth and Progression through the Establishment of an Immunosuppressive Microenvironment

Author: Padma Murthi, Roland Abi Nahed, Deborah Reynaud, Vincent Sapin, Nadia Alfaidy, Christophe Battail, Mohamed Benharouga, Nicolas Lemaitre, Touria Aboussaouira, Pierre-Adrien Bolze, Wael Traboulsi, Rima Slim, Odile Filhol, Pascale Hoffmann, Houssine Boufettal, Frederic Sergent, BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), CEA- Saclay (CEA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Physiologie cellulaire et végétale (LPCV), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Georgetown University Medical Center, Génétique, Reproduction et Développement (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne (UCA), CHU Clermont-Ferrand, Ibn Rochd University Hospital of Casablanca, University Hassan II of Casablanca, Morocco., Centre Hospitalier Universitaire [Grenoble] (CHU), Monash Biomedicine Discovery Institute, Monash University [Clayton], University of Melbourne, McGill University = Université McGill [Montréal, Canada], Mécanisme de l’Angiogenèseet des BarrièresBiologiques (MAB2), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Alfaidy, Nadia, and ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017)
Subjects: 0301 basic medicine, Cancer Research, orthotopic model of choriocarcinoma, [SDV.BDLR.RA]Life Sciences [q-bio]/Reproductive Biology/Asexual reproduction, Article, Gestational choriocarcinoma, Immune tolerance, Proinflammatory cytokine, NLRP7, 03 medical and health sciences, 0302 clinical medicine, Immune system, Downregulation and upregulation, medicine, choriocarcinoma, tumor microenvironment, [SDV.BDLR.RA] Life Sciences [q-bio]/Reproductive Biology/Asexual reproduction, reproductive and urinary physiology, RC254-282, Tumor microenvironment, Gene knockdown, business.industry, Choriocarcinoma, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, 3. Good health, hydatidiform mole, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, embryonic structures, Cancer research, business, maternal immune tolerance
Abstract: The inflammatory gene NLRP7 is the major gene responsible for recurrent complete hydatidiform moles (CHM), an abnormal pregnancy that can develop into gestational choriocarcinoma (CC). However, the role of NLRP7 in the development and immune tolerance of CC has not been investigated. Three approaches were employed to define the role of NLRP7 in CC development: (i) a clinical study that analyzed human placenta and sera collected from women with normal pregnancies, CHM or CC, (ii) an in vitro study that investigated the impact of NLRP7 knockdown on tumor growth and organization, and (iii) an in vivo study that used two CC mouse models, including an orthotopic model. NLRP7 and circulating inflammatory cytokines were upregulated in tumor cells and in CHM and CC. In tumor cells, NLRP7 functions in an inflammasome-independent manner and promoted their proliferation and 3D organization. Gravid mice placentas injected with CC cells invalidated for NLRP7, exhibited higher maternal immune response, developed smaller tumors, and displayed less metastases. Our data characterized the critical role of NLRP7 in CC and provided evidence of its contribution to the development of an immunosuppressive maternal microenvironment that not only downregulates the maternal immune response but also fosters the growth and progression of CC.
Published: 2021

18. NLRP7 is increased in human idiopathic fetal growth restriction and plays a critical role in trophoblast differentiation

Author: Wael Traboulsi, Déborah Reynaud, Padma Murthi, Nadia Alfaidy, M. N. Dieudonné, A. Wetzel, M. Dakouane-Giudicelli, R. Abi Nahed, Mohamed Benharouga, Anthony J. Borg, Vincent Sapin, Sophie Brouillet, Invasion mechanisms in angiogenesis and cancer (IMAC), Biologie du Cancer et de l'Infection (BCI ), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM), Hudson Institute of Medical Research [Clayton], The Royal Women's Hospital, Laboratoire d’Aide à la Procréation, Département de Génétique et Procréation (CECOS), Hôpital Couple Enfant de Grenoble-CHU de Grenoble, Génétique, Reproduction et Développement (GReD), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Gamètes, implantation, gestation (GIG), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie des Métaux (BioMet), Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Department of Obstetrics and Gynaecology, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG)
Subjects: Adult, Placenta, Cellular differentiation, Interleukin-1beta, Inflammation, Biology, Cell Line, NLRP7, Inflammasome, Andrology, Pathogenesis, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, Pregnancy, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Drug Discovery, medicine, Humans, Hypoxia, Receptor, reproductive and urinary physiology, Genetics (clinical), Adaptor Proteins, Signal Transducing, 030304 developmental biology, 0303 health sciences, Fetal Growth Retardation, Interleukin-18, Trophoblast, Cell Differentiation, FGR, Trophoblasts, 3. Good health, Pregnancy Trimester, First, Trophoblast invasion, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, medicine.anatomical_structure, 030220 oncology & carcinogenesis, embryonic structures, Molecular Medicine, Female, medicine.symptom, medicine.drug
Abstract: International audience; Fetal growth restriction (FGR) the leading cause of perinatal mortality and morbidity is highly related to abnormal placental development, and placentas from FGR pregnancies are often characterized by increased inflammation. However, the mechanisms of FGR-associated inflammation are far from being understood. NLRP7, a member of a family of receptors involved in the innate immune responses, has been shown to be associated with gestational trophoblastic diseases. Here, we characterized the expression and the functional role of NLRP7 in the placenta and investigated its involvement in the pathogenesis of FGR. We used primary trophoblasts and placental explants that were collected during early pregnancy, and established trophoblast-derived cell lines, human placental villi, and serum samples from early pregnancy (n = 38) and from FGR (n = 40) and age-matched controls (n = 32). Our results show that NLRP7 (i) is predominantly expressed in the trophoblasts during the hypoxic period of placental development and its expression is upregulated by hypoxia and (ii) increases trophoblast proliferation ([3H]-thymidine) and controls the precocious differentiation of trophoblasts towards syncytium (syncytin 1 and 2 and β-hCG production and xCELLigence analysis) and towards invasive extravillous trophoblast (2D and 3D cultures). We have also demonstrated that NLRP7 inflammasome activation in trophoblast cells increases IL-1β, but not IL-18 secretion. In relation to the FGR, we demonstrated that major components of NLRP7 inflammasome machinery are increased and that IL-1β but not IL-18 circulating levels are increased in FGR. Altogether, our results identified NLRP7 as a critical placental factor and provided evidence for its deregulation in FGR. NLRP7 inflammasome is abundantly expressed by trophoblast cells. It is regulated by a key parameter of placental development, hypoxia. It controls trophoblast proliferation, migration, and invasion and exhibits anti-apoptotic role. NLRP7 machinery is deregulated in FGR pregnancies.
Published: 2019

19. Evidence-Based View of Safety and Effectiveness of Prokineticin Receptors Antagonists during Pregnancy

Author: Constance Collet, C. Marquette, Déborah Reynaud, Wael Traboulsi, Qun-Yong Zhou, Nadia Alfaidy, Pascale Hoffmann, Padma Murthi, Roland Abi Nahed, Mohamed Benharouga, Gianfranco Balboni, Frederic Sergent, Mécanisme de l’Angiogenèseet des BarrièresBiologiques (MAB2), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), and ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017)
Subjects: Angiogenesis, [SDV]Life Sciences [q-bio], Medicine (miscellaneous), Bioinformatics, General Biochemistry, Genetics and Molecular Biology, Article, Preeclampsia, 03 medical and health sciences, chemistry.chemical_compound, angiogenesis, 0302 clinical medicine, vascularization, trophoblast invasion, medicine, EG-VEGF, Receptor, lcsh:QH301-705.5, 030304 developmental biology, prokineticins, 0303 health sciences, Pregnancy, prokineticin antagonists, therapy, business.industry, Trophoblast, pregnancy pathologies, homeobox genes, medicine.disease, Prokineticin, endothelial cells, 3. Good health, Vascular endothelial growth factor, vessel development, medicine.anatomical_structure, chemistry, lcsh:Biology (General), pregnancy, business, 030217 neurology & neurosurgery, Endocrine gland
Abstract: Endocrine gland derived vascular endothelial growth factor (EG-VEGF) is a canonical member of the prokineticin (PROKs) family. It acts via the two G-protein coupled receptors, namely PROKR1 and PROKR2. We have recently demonstrated that EG-VEGF is highly expressed in the human placenta, contributes to placental vascularization and growth and that its aberrant expression is associated with pregnancy pathologies including preeclampsia and fetal growth restriction. These findings strongly suggested that antagonization of its receptors may constitute a potential therapy for the pregnancy pathologies. Two specific antagonists of PROKR1 (PC7) and for PROKR2 (PKRA) were reported to reverse PROKs adverse effects in other systems. In the view of using these antagonists to treat pregnancy pathologies, a proof of concept study was designed to determine the biological significances of PC7 and PKRA in normal pregnancy outcome. PC7 and PKRA were tested independently or in combination in trophoblast cells and during early gestation in the gravid mouse. Both independent and combined treatments uncovered endogenous functions of EG-VEGF. The independent use of antagonists distinctively identified PROKR1 and PROKR2-mediated EG-VEGF signaling on trophoblast differentiation and invasion, thereby enhancing feto-placental growth and pregnancy outcome. Thus, our study provides evidence for the potential safe use of PC7 or PKRA to improve pregnancy outcome.
Published: 2021

20. Vascular endothelial growth factor (VEGF) and Endocrine gland-VEGF (EG-VEGF) are down regulated in head and neck cancer

Author: Mohammed Benlahfid, Wael Traboulsi, Nadia Alfaidy, Mustapha Sidqui, Mohamed Benharouga, Touria Aboussaouira, Si Mohamed Bouzoubaa, Chouaib Rifki, Sophie Brouillet, Ibn Rochd University Hospital of Casablanca, University Hassan II of Casablanca, Morocco., Invasion mechanisms in angiogenesis and cancer (IMAC), Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Laboratoire d’Aide à la Procréation, Département de Génétique et Procréation (CECOS), Hôpital Couple Enfant de Grenoble-CHU de Grenoble, Biologie des Métaux (BioMet ), Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG)
Subjects: Oncology, CD31, Male, Vascular Endothelial Growth Factor A, Angiogenesis, Epulis, PROKR2, PROKR1, CD34, chemistry.chemical_compound, 0302 clinical medicine, 030223 otorhinolaryngology, Receptor, Immunohistochemistry, VEGF, Vascular endothelial growth factor, Head and Neck Neoplasms, 030220 oncology & carcinogenesis, Disease Progression, Female, OSCC, Ki67, Adult, medicine.medical_specialty, Down-Regulation, Enzyme-Linked Immunosorbent Assay, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 03 medical and health sciences, Young Adult, Internal medicine, Endocrine Glands, medicine, Biomarkers, Tumor, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, EG-VEGF, business.industry, Head and neck cancer, medicine.disease, HNC, stomatognathic diseases, Otorhinolaryngology, chemistry, Vascular Endothelial Growth Factor, Endocrine-Gland-Derived, business
Abstract: International audience; Objective To characterise the role of VEGF, EG-VEGF and its receptors in the development and progression of HNC. Design Human serum and tissues samples were collected from healthy, epulis and HNC patients and used for ELISA assays and immunohistochemistry studies, respectively. Setting Ibn Rochd Hospital of Casablanca (Morocco), INSERM and University of Grenoble Alpes (France). Participants We used serum from 64 patients with head and neck cancers and from 71 controls without general pathology. Tissues samples were collected from seven patients with OSCC and from seven patients with Epulis. Main outcome measures We compared circulating VEGF and EG-VEGF in normal and HNC patients and determined the expression, localisation and quantification of VEGF, EG-VEGF and its receptors; PROKR1 and PROKR2 as well as Ki67, CD31 and CD34 in OSCC and Epulis patients. Results Both EG-VEGF and VEGF circulating levels were significantly decreased in the HNC (P < .01). OSCC patients expressed less EG-VEGF and VEGF proteins, higher PROKR1 and PROKR2 with no change in CD31 and CD34 levels. A significant increase in Ki67 was observed in OSCC. Conclusions We demonstrated that circulating VEGF and EG-VEGF are downregulated in HNC patients and in OSCC tissue. EG-VEGF receptors were increased in OSCC, along with a stabilisation of two key markers of angiogenesis. These findings strongly suggest that downregulation of angiogenesis in HNC might explain its moderate metastatic feature.
Published: 2020

21. Protein kinase CK2 contributes to placental development: physiological and pathological implications

Author: Nicolas Lemaitre, Claude Cochet, Daniel Vaiman, Déborah Reynaud, Odile Filhol, Mohamed Benharouga, Nadia Alfaidy, Roland Abi Nahed, Solene Lartigue, Caroline Roelants, Invasion mechanisms in angiogenesis and cancer (IMAC), Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Inovarion, Inovarion [Paris], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biologie des Métaux (BioMet), Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Biologie des Métaux (BioMet ), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Adult, Invasion de trophoblastes, Modèle animal, Prééclampsie, Adolescent, Protein subunit, Placenta, Biology, Preeclampsia, Andrology, Mice, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Pre-Eclampsia, Pregnancy, In vivo, Cell Line, Tumor, Drug Discovery, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Animals, Humans, Casein Kinase II, Genetics (clinical), reproductive and urinary physiology, Trophoblast, medicine.disease, Molecular medicine, Placentation, In vitro, Trophoblasts, Mice, Inbred C57BL, Disease Models, Animal, Pregnancy Trimester, First, Protéine kinase CK2, medicine.anatomical_structure, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, embryonic structures, Molecular Medicine, Female, Ex vivo, 030215 immunology
Abstract: International audience; Preeclampsia (PE) is the most threatening pathology of human pregnancy. Its development is thought to be due to a failure in the invasion of trophoblast cells that establish the feto-maternal circulation. Protein kinase CK2 is a ubiquitous enzyme reported to be involved in the control of cell invasion. CK2 consists of two subunits, a catalytic subunit, CK2α, and a regulatory subunit, CK2β. To date, no data exist regarding the expression and role of this enzyme in normal and PE pregnancies. We performed studies, at the clinical level using distinctive cohorts from early pregnancy (n = 24) and from PE (n = 23) and age-matched controls (n = 28); in vitro, using trophoblast cell lines; ex vivo, using placental explants; and in vivo, using PE mouse models. We demonstrated that (i) CK2 is more expressed during the late first trimester of pregnancy and is mainly localized in differentiated trophoblast cells, (ii) the inhibition of its enzymatic activity decreased the proliferation, migration, invasion, and syncytialization of trophoblast cells, both in 2D and 3D culture systems, and (iii) CK2 activity and the CK2α/CK2β protein ratio were increased in PE human placentas. The pattern and profile of CK2 expression were confirmed in gravid mice along with an increase in the PE mouse models. Altogether, our results demonstrate that CK2 plays an essential role in the establishment of the feto-maternal circulation and that its deregulation is associated with PE development. The increase in CK2 activity in PE might constitute a compensatory mechanism to ensure proper pregnancy progress.
Published: 2020

22. Endocrine gland-derived vascular endothelial growth factor (EG-VEGF) and its receptor PROKR2 are associated to human colorectal cancer progression and peritoneal carcinomatosis

Author: Abdelaziz Fadil, Mohammed Benlahfid, Mohamed Benharouga, Driss Erguibi, Mehdi Karkouri, Khalid Elhattabi, Hicham Elattar, Wael Traboulsi, Yassine Fahmi, Frederic Sergent, Nadia Alfaidy, Touria Aboussaouira, Faculty of Medicine and Pharmacy, University Hassan II Casablanca, Laboratory of Scientific and Clinical Researches in Cancerous Pathologies, Biologie du Cancer et de l'Infection (BCI ), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Ibn Rochd University Hospital of Casablanca, University Hassan II of Casablanca, Morocco., Laboratory of anatomopathology Moulay Driss 1e⁢r, Casablanca, Morocco., Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), and Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG)
Subjects: Adult, Male, 0301 basic medicine, Cancer Research, Adolescent, Receptors, Peptide, Colorectal cancer, colorectal cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, Prokineticin, Receptors, G-Protein-Coupled, Metastasis, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Risk Factors, Genetics, Humans, Medicine, Endocrine system, EG-VEGF, Risk factor, Receptor, Peritoneal Neoplasms, Aged, business.industry, peritoneal carcinomatosis, General Medicine, Middle Aged, medicine.disease, Immunohistochemistry, 3. Good health, Vascular endothelial growth factor, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, 030104 developmental biology, Oncology, chemistry, 030220 oncology & carcinogenesis, Disease Progression, Cancer research, Female, Vascular Endothelial Growth Factor, Endocrine-Gland-Derived, Colorectal Neoplasms, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Endocrine gland
Abstract: International audience; BACKGROUND:The highest risk factor for mortality among malignant tumors is metastasis. Endocrine gland-derived vascular endothelial growth factor (EG-VEGF) is an angiogenic factor which biological activity is mediated via two G protein-coupled receptors, prokineticin receptor1 (PROKR1) and PROKR2. Recent studies suggested that EG-VEGF expression is deregulated in multiple cancers including colorectal cancer (CRC).METHODS:Using distinctive CRC and peritoneal carcinomatosis (PC) cohorts and corresponding control cohort, we determined the circulating levels of EG-VEGF and its in situ expression, and that of its related receptors.RESULTS:Circulating EG-VEGF levels were significantly increased in patients with metastatic PC compared to CRC and control patients (p< 0.05). Furthermore, according to clinicopathologic examinations, local EG-VEGF expression correlated with higher tumor and nodal stages (p< 0.001) of CRC. EG-VEGF and PROKR2 were highly expressed in colorectal primary lesions compared to positive controls. PROKR1 expression was lower and did not change in tumor specimens. Also, EG-VEGF and its receptor PROKR2 were differentially expressed in the colorectal primary lesions and in the control groups.CONCLUSION:Altogether these findings suggest that EG-VEGF/receptors system might be an important actor in the CRC progression into PC and might be involved in the ability of tumor cells to invade other organs. Circulating EG-VEGF could be proposed as a prognostic marker in human CRC and its progression into PC.
Published: 2018

23. Involvement of the Prion Protein in the Protection of the Human Bronchial Epithelial Barrier Against Oxidative Stress

Author: Pierre Richaud, Mariam El Khatib, Sylvain Chauvet, Micheline El Khoury, Johanna Cormenier, Christelle Coraux, Wael Zeinyeh, Mohamed Benharouga, Laurence Macari, Nadia Alfaidy, Isabelle Michaud-Soret, Amal Kouadri, Biologie des Métaux (BioMet), Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Biosciences et Biotechnologies d'Aix-Marseille (ex-IBEB) (BIAM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Pathologies Pulmonaires et Plasticité Cellulaire - UMR-S 1250 (P3CELL), Université de Reims Champagne-Ardenne (URCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), GON, Nathalie, Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Copper Sulfate, Physiology, animal diseases, Clinical Biochemistry, Bronchial epithelium, Bronchi, Oxidative phosphorylation, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, medicine.disease_cause, Biochemistry, Desmoglein, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Prion Proteins, Cell Line, Adherens junction, 03 medical and health sciences, Cell polarity, medicine, Humans, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Molecular Biology, General Environmental Science, Messenger RNA, 030102 biochemistry & molecular biology, biology, Tight junction, Chemistry, Desmoplakin, Cell Polarity, Epithelial Cells, Adherens Junctions, Cell Biology, Cell biology, nervous system diseases, 030104 developmental biology, Prion protein, A549 Cells, Oxidative stress, biology.protein, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, General Earth and Planetary Sciences, Junctional proteins, Copper
Abstract: International audience; AIM: Bronchial epithelium acts as a defensive barrier against inhaled pollutants and microorganisms. This barrier is often compromised in inflammatory airway diseases that are characterized by excessive oxidative stress responses, leading to bronchial epithelial shedding, barrier failure, and increased bronchial epithelium permeability. Among proteins expressed in the junctional barrier and participating to the regulation of the response to oxidative and to environmental stresses is the cellular prion protein (PrPC). However, the role of PrPC is still unknown in the bronchial epithelium. Herein, we investigated the cellular mechanisms by which PrPC protein participates into the junctional complexes formation, regulation, and oxidative protection in human bronchial epithelium.RESULTS: Both PrPC messenger RNA and mature protein were expressed in human epithelial bronchial cells. PrPC was localized in the apical domain and became lateral, at high degree of cell polarization, where it colocalized and interacted with adherens (E-cadherin/γ-catenin) and desmosomal (desmoglein/desmoplakin) junctional proteins. No interaction was detected with tight junction proteins. Disruption of such interactions induced the loss of the epithelial barrier. Moreover, we demonstrated that PrPC protection against copper-associated oxidative stress was involved in multiple processes, including the stability of adherens and desmosomal junctional proteins.INNOVATION: PrPC is a pivotal protein in the protection against oxidative stress that is associated with the degradation of adherens and desmosomal junctional proteins.CONCLUSION: Altogether, these results demonstrate that the loss of the integrity of the epithelial barrier by oxidative stress is attenuated by the activation of PrPC expression, where deregulation might be associated with respiratory diseases.
Published: 2019

24. Risk factors and poor prognostic factors of preeclampsia in Ibn Rochd University Hospital of Casablanca: about 401 preeclamptic cases

Author: Mohamed Benharouga, Touria Aboussaouira, Souadou Cissoko, Nadia Alfaidy, Meriem Benfateh, Naïma Samouh, Jean-Jacques Feige, Houssine Boufettal, Unité de Culture Cellulaire, CED, Faculté de Médecine et de Pharmacie, Service C de Gynécologie, CHU Ibn Rochd, Faculté de Médecine et de Pharmacie, Angiogenèse hormono-regulée et angiogenèse tumorale (LAPV), Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Médecine et Pharmacie Casablanca, Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: medicine.medical_specialty, Context (language use), Prenatal care, 030204 cardiovascular system & hematology, Abortion, Preeclampsia, 03 medical and health sciences, 0302 clinical medicine, Epidemiology, medicine, risk factors, Case Series, 030212 general & internal medicine, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, Obstetrics, business.industry, Incidence (epidemiology), fetal prognostic, Gestational age, General Medicine, medicine.disease, maternal prognostic, 3. Good health, Gestation, business
Abstract: International audience; Preeclampsia is a gestational pathology that complicates 2 to 8% of pregnancies and is one of the major causes of maternal and fetal morbidity and mortality worldwide. The aim of this work was to study the epidemiological profile of preeclampsia in Casablanca and to identify risk factors as well as factors of poor maternal and fetal prognosis. 401 preeclamptic cases were collected in the gynecology-obstetrics "C" Service of Lalla Meryem Maternity of Ibn Rochd University Hospital of Casablanca (2010-2011) were included in this study and a statistical analysis with the SPSS software version (16.0) was performed. We used the Chi-2 test to analyze qualitative variables and Student's test and ANOVA (analysis of variance) for quantitative variables. The incidence of preeclampsia was (7.1%). The epidemiological profile was that of a primipara (57.6%), average age 30 years and (66.8%) of pregnancies were not followed. Multiparity was a factor of poor maternal prognosis (p = 0.007). The low gestational age and no prenatal care were factors of maternal as well as fetal prognosis. Risk factors frequently found in our patients were obesity (15.21%) and chronic hypertension (5.73%) as vascular-renal history; abortion (16.46%) and perinatal death (5.24%) as obstetric history. Preeclampsia is a common obstetric pathology in our context. Better prenatal care and early diagnosis could reduce its incidence.
Published: 2018

25. Erratum to: EG-VEGF Maintenance Over Early Gestation to Develop a Pregnancy-Induced Hypertensive Animal Model

Author: Déborah, Reynaud, Frédéric, Sergent, Roland, Abi Nahed, Sophie, Brouillet, Mohamed, Benharouga, and Nadia, Alfaidy
Published: 2018

26. Erratum to: EG-VEGF Maintenance Over Early Gestation to Develop a Pregnancy-Induced Hypertensive Animal Model

Author: Sophie Brouillet, Déborah Reynaud, Roland Abi Nahed, Nadia Alfaidy, Frederic Sergent, and Mohamed Benharouga
Subjects: Andrology, business.industry, Early gestation, Hypertensive animal, Pregnancy induced, Medicine, business
Published: 2018

27. EG-VEGF Maintenance Over Early Gestation to Develop a Pregnancy-Induced Hypertensive Animal Model

Author: Déborah, Reynaud, Frédéric, Sergent, Roland, Abi Nahed, Sophie, Brouillet, Mohamed, Benharouga, and Nadia, Alfaidy
Subjects: Male, Disease Models, Animal, Mice, Pre-Eclampsia, Pregnancy, Animals, Humans, Female, Vascular Endothelial Growth Factor, Endocrine-Gland-Derived, Hypertension, Pregnancy-Induced, Trophoblasts
Abstract: During the last decade, multiple animal models have been developed to mimic hallmarks of pregnancy-induced hypertension (PIH) diseases, which include gestational hypertension, preeclampsia (PE), or eclampsia. Converging in vitro, ex vivo, and clinical studies from our group strongly suggested the potential involvement of the new angiogenic factor EG-VEGF (endocrine gland-derived-VEGF) in the development of PIH. Here, we described the protocol that served to demonstrate that maintenance of EG-VEGF production over 11.5 days post coitus (dpc) in the gravid mice caused the development of PIH. The developed model exhibited most hallmarks of preeclampsia.
Published: 2017

28. EG-VEGF Maintenance Over Early Gestation to Develop a Pregnancy-Induced Hypertensive Animal Model

Author: Déborah Reynaud, Mohamed Benharouga, Roland Abi Nahed, Sophie Brouillet, Frederic Sergent, and Nadia Alfaidy
Subjects: 0301 basic medicine, Gestational hypertension, Pregnancy, Eclampsia, business.industry, Glomerulosclerosis, Physiology, medicine.disease, female genital diseases and pregnancy complications, 3. Good health, Preeclampsia, 03 medical and health sciences, 030104 developmental biology, medicine.anatomical_structure, Placenta, embryonic structures, medicine, Endocrine system, business, reproductive and urinary physiology, Ex vivo
Abstract: During the last decade, multiple animal models have been developed to mimic hallmarks of pregnancy-induced hypertension (PIH) diseases, which include gestational hypertension, preeclampsia (PE), or eclampsia. Converging in vitro, ex vivo, and clinical studies from our group strongly suggested the potential involvement of the new angiogenic factor EG-VEGF (endocrine gland-derived-VEGF) in the development of PIH. Here, we described the protocol that served to demonstrate that maintenance of EG-VEGF production over 11.5 days post coitus (dpc) in the gravid mice caused the development of PIH. The developed model exhibited most hallmarks of preeclampsia.
Published: 2017

29. Antagonism of EG-VEGF Receptors as Targeted Therapy for Choriocarcinoma Progression In Vitro and In Vivo

Author: Touria Aboussaouira, Rima Slim, Pierre Adrien Bolze, François Mallet, Nadia Alfaidy, Philippe Sauthier, Houssine Boufettal, Jean-Jacques Feige, Sophie Brouillet, Mohamed Benharouga, Aude Salomon, Wael Traboulsi, Valentina Onnis, Mohammed Benlahfid, Frederic Sergent, Gianfranco Balboni, Qun-Yong Zhou, Pascale Hoffmann, INSERM, Institut national de la santé et de la recherche médicale (INSERM), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut de Biosciences et de Biotechnologies de Grenoble (ex-IRTSV) (BIG), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Faculty of Medicine and Pharmacy, University Hassan II Casablanca, Obstetrics and Gynecology Department, Ibn Rochd Hospital of Casablanca, Laboratoire d’Aide à la Procréation, Département de Génétique et Procréation (CECOS), Hôpital Couple Enfant de Grenoble-CHU de Grenoble, Department of Obstetrics and Gynaecology, University Hospital of Grenoble, La Tronche, France, Departments of Human Genetics and Oncology, McGill University Health Center [Montreal] (MUHC), Department of Pharmacology [Irvine], University of California [Irvine] (UC Irvine), University of California (UC)-University of California (UC), Department of Life and Environmental Sciences, Università degli Studi di Cagliari = University of Cagliari (UniCa), Department of Gynecological Surgery and Oncology, Obstetrics, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), French Reference Center for Gestational Trophoblastic Diseases, University Hospital Lyon Sud, Joint Unit Hospices Civils de Lyon-bioMerieux, Cancer Biomarkers Research Group, University Hospital Lyon Sud, Physiopathologie de l'immunodépression associée aux réponses inflammatoires systémiques / Pathophysiology of Injury-induced Immunosuppression (PI3), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Unité Grenoble, Grenoble, France.University Grenoble-Alpes, Grenoble, France., Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), University of California [Irvine] (UCI), University of California-University of California, University of Cagliari, Physiopathologie de l'immunodépression associée aux réponses inflammatoires systémiques - EA 7426 (PI3), Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Grenoble Alpes (UGA), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), INSERM, Institut national de la santé et de la recherche médicale ( INSERM ), Institut de Biosciences et de Biotechnologies de Grenoble (ex-IRTSV) ( BIG ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), Laboratoire d’Aide à la Procréation, Département de Génétique et Procréation ( CECOS ), McGill University Health Centre Research Institute, Montréal, Quebec, Canada., University of California [Irvine] ( UCI ), Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Physiopathologie de l'immunodépression associée aux réponses inflammatoires systémiques - EA 7426 ( PI3 ), Institut des Sciences Pharmaceutiques et Biologiques ( ISPB ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Université Claude Bernard Lyon 1 ( UCBL ), Laboratoire de Chimie et Biologie des Métaux ( LCBM - UMR 5249 ), and Université Joseph Fourier - Grenoble 1 ( UJF ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA )
Subjects: 0301 basic medicine, Placental growth factor, Cancer Research, Pathology, medicine.medical_specialty, medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Targeted therapy, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Placenta, medicine, Receptor, [ SDV.MHEP.GEO ] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Gestational trophoblastic disease, Choriocarcinoma, Trophoblast, medicine.disease, 3. Good health, Vascular endothelial growth factor, 030104 developmental biology, medicine.anatomical_structure, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Oncology, chemistry, 030220 oncology & carcinogenesis, Cancer research
Abstract: Purpose: Choriocarcinoma (CC) is the most malignant gestational trophoblastic disease that often develops from complete hydatidiform moles (CHM). Neither the mechanism of CC development nor its progression is yet characterized. We recently identified endocrine gland–derived vascular endothelial growth factor (EG-VEGF) as a novel key placental growth factor that controls trophoblast proliferation and invasion. EG-VEGF acts via two receptors, PROKR1 and PROKR2. Here, we demonstrate that EG-VEGF receptors can be targeted for CC therapy. Experimental Design: Three approaches were used: (i) a clinical investigation comparing circulating EG-VEGF in control (n = 20) and in distinctive CHM (n = 38) and CC (n = 9) cohorts, (ii) an in vitro study investigating EG-VEGF effects on the CC cell line JEG3, and (iii) an in vivo study including the development of a novel CC mouse model, through a direct injection of JEG3-luciferase into the placenta of gravid SCID-mice. Results: Both placental and circulating EG-VEGF levels were increased in CHM and CC (×5) patients. EG-VEGF increased JEG3 proliferation, migration, and invasion in two-dimensional (2D) and three-dimensional (3D) culture systems. JEG3 injection in the placenta caused CC development with large metastases compared with their injection into the uterine horn. Treatment of the animal model with EG-VEGF receptor's antagonists significantly reduced tumor development and progression and preserved pregnancy. Antibody-array and immunohistological analyses further deciphered the mechanism of the antagonist's actions. Conclusions: Our work describes a novel preclinical animal model of CC and presents evidence that EG-VEGF receptors can be targeted for CC therapy. This may provide safe and less toxic therapeutic options compared with the currently used multi-agent chemotherapies. Clin Cancer Res; 23(22); 7130–40. ©2017 AACR.
Published: 2017

30. PPARγ controls pregnancy outcome through activation of EG-VEGF: new insights into the mechanism of placental development

Author: Wael Traboulsi, Aude Salomon, Valentina Onnis, Béatrice Desvergne, Cenzo Congiu, Mohamed Benharouga, Carine Winkler, Jean-Jacques Feige, Thierry Fournier, Sophie Brouillet, Qun-Yong Zhou, Pascale Hoffmann, Nadia Alfaidy, Vanessa Garnier, Biologie du Cancer et de l'Infection ( BCI - UMR S1036 ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Grenoble Alpes ( UGA ), Department of Life and Environmental Sciences, University of Cagliari, Physiopathologie et Pharmacotoxicologie Placentaire Humaine ( U1139 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), PremUp Foundation, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Sorbonne Universités-Université Paris Descartes - Paris 5 ( UPD5 ) -CHI Créteil-Institut de Recherche pour le Développement ( IRD ) -Université Paris-Sud - Paris 11 ( UP11 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Diderot - Paris 7 ( UPD7 ), Center for Integrative Genomics - Institute of Bioinformatics, Génopode ( CIG ), University of Lausanne, Département de Gynécologie, Obstétrique et Médecine de la Reproduction, CHU Grenoble, Department of Pharmacology [Irvine], University of California [Irvine] ( UCI ), Laboratoire de Chimie et Biologie des Métaux ( LCBM - UMR 5249 ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Physiopathologie et Pharmacotoxicologie Placentaire Humaine (U1139), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-CHI Créteil-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL)-Université de Lausanne = University of Lausanne (UNIL), University of California [Irvine] (UC Irvine), University of California (UC)-University of California (UC), Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Descartes - Paris 5 (UPD5)-CHI Créteil-Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7), Université de Lausanne (UNIL)-Université de Lausanne (UNIL), University of California [Irvine] (UCI), University of California-University of California, Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Universités-Université Paris Descartes - Paris 5 (UPD5)-CHI Créteil-Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7), and Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG)
Subjects: Male, Pyridines, Physiology, Placenta, Endocrinology, Diabetes and Metabolism, Peroxisome proliferator-activated receptor, ANGIOGENESIS, HUMAN FETOPLACENTAL VASCULOGENESIS, Mice, trophoblast invasion, Pregnancy, Cricetinae, human pregnancy, MOLECULAR CHARACTERIZATION, Receptor, [ SDV.MHEP.GEO ] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Cells, Cultured, chemistry.chemical_classification, [ SDV.MHEP.PHY ] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Pregnancy Outcome, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [ SDV.BDLR ] Life Sciences [q-bio]/Reproductive Biology, medicine.anatomical_structure, embryonic structures, Benzamides, Female, EXPRESSION, Transcriptional Activation, medicine.medical_specialty, PATHOLOGICAL IMPLICATIONS, Mice, Transgenic, Biology, Rosiglitazone, endocrine gland-derived vascular endothelial growth factor, PROTEIN-COUPLED RECEPTORS, In vivo, Physiology (medical), Internal medicine, medicine, Animals, Humans, Embryo Implantation, OXYGEN REGULATION, Placentation, Trophoblast, Prokineticin receptor 1, Embryo, Mammalian, EXTRAVILLOUS TROPHOBLASTS, peroxisome proliferator-activated receptor-gamma knockout, PPAR gamma, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Endocrinology, chemistry, ENDOTHELIAL GROWTH-FACTOR, CELLS, Thiazolidinediones, Vascular Endothelial Growth Factor, Endocrine-Gland-Derived, Ex vivo
Abstract: PPARγ-deficient mice die at E9.5 due to placental abnormalities. The mechanism by which this occurs is unknown. We demonstrated that the new endocrine factor EG-VEGF controls the same processes as those described for PPARγ, suggesting potential regulation of EG-VEGF by PPARγ. EG-VEGF exerts its functions via prokineticin receptor 1 (PROKR1) and 2 (PROKR2). This study sought to investigate whether EG-VEGF mediates part of PPARγ effects on placental development. Three approaches were used: 1) in vitro, using human primary isolated cytotrophoblasts and the extravillous trophoblast cell line (HTR-8/SVneo); 2) ex vivo, using human placental explants ( n = 46 placentas); and 3) in vivo, using gravid wild-type PPARγ+/− and PPARγ−/− mice. Major processes of placental development that are known to be controlled by PPARγ, such as trophoblast proliferation, migration, and invasion, were assessed in the absence or presence of PROKR1 and PROKR2 antagonists. In both human trophoblast cell and placental explants, we demonstrated that rosiglitazone, a PPARγ agonist, 1) increased EG-VEGF secretion, 2) increased EG-VEGF and its receptors mRNA and protein expression, 3) increased placental vascularization via PROKR1 and PROKR2, and 4) inhibited trophoblast migration and invasion via PROKR2. In the PPARγ−/− mouse placentas, EG-VEGF levels were significantly decreased, supporting an in vivo control of EG-VEGF/PROKRs system during pregnancy. The present data reveal EG-VEGF as a new mediator of PPARγ effects during pregnancy and bring new insights into the fine mechanism of trophoblast invasion.
Published: 2015

31. Antagonism of EG-VEGF Receptors as Targeted Therapy for Choriocarcinoma Progression

Author: Wael, Traboulsi, Frédéric, Sergent, Houssine, Boufettal, Sophie, Brouillet, Rima, Slim, Pascale, Hoffmann, Mohammed, Benlahfid, Qun Y, Zhou, Gianfranco, Balboni, Valentina, Onnis, Pierre A, Bolze, Aude, Salomon, Philippe, Sauthier, François, Mallet, Touria, Aboussaouira, Jean J, Feige, Mohamed, Benharouga, and Nadia, Alfaidy
Subjects: Receptors, Peptide, Gene Expression, Antineoplastic Agents, Prognosis, Xenograft Model Antitumor Assays, Receptors, G-Protein-Coupled, Disease Models, Animal, Mice, Cell Transformation, Neoplastic, Genes, Reporter, Cell Line, Tumor, Biomarkers, Tumor, Disease Progression, Animals, Humans, Female, Vascular Endothelial Growth Factor, Endocrine-Gland-Derived, Choriocarcinoma, Molecular Targeted Therapy, Signal Transduction
Published: 2017

32. Prion Protein Expression and Functional Importance in Developmental Angiogenesis: Role in Oxidative Stress and Copper Homeostasis

Author: Catherine Aude-Garcia, Jean-Marc Moulis, P. Hoffmann, Pierre Richaud, Annie Andrieux, Aude Salomon, Yasmina Saoudi, Jean-Jacques Feige, Mohamed Benharouga, Nadia Alfaidy, Sylvain Chauvet, Sandrine Donadio-Andrei, Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Joseph Fourier - Grenoble 1 (UJF), Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), INSERM U836, équipe 1, Physiopathologie du cytosquelette, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie végétale et microbiologie environnementale - UMR7265 (BVME), Institut de Biosciences et Biotechnologies d'Aix-Marseille (ex-IBEB) (BIAM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Département de Gynécologie, Obstétrique et Médecine de la Reproduction, CHU Grenoble, Groupe Physiopathologie du Cytosquelette (GPC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF), CNRS (LCBM-UMR 5249) INSERM (U1036) UJF CEA/DSV/iRTSV, Andrieux, Annie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Grenoble Institut des Neurosciences (GIN)
Subjects: Physiology, Placenta, animal diseases, Clinical Biochemistry, Pregnancy Proteins, medicine.disease_cause, Biochemistry, Transcriptome, Mice, 0302 clinical medicine, Cell Movement, Pregnancy, Cricetinae, Homeostasis, reproductive and urinary physiology, General Environmental Science, Mice, Knockout, chemistry.chemical_classification, 0303 health sciences, Fetal Growth Retardation, Cell Death, Cell Hypoxia, Trophoblasts, Up-Regulation, 3. Good health, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Knockout mouse, Female, Programmed cell death, Neovascularization, Physiologic, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Cell Line, 03 medical and health sciences, Downregulation and upregulation, medicine, Animals, Humans, PrPC Proteins, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Molecular Biology, Cell Proliferation, 030304 developmental biology, Reactive oxygen species, Trophoblast, Cell Biology, Hypoxia-Inducible Factor 1, alpha Subunit, nervous system diseases, Mice, Inbred C57BL, Oxidative Stress, chemistry, General Earth and Planetary Sciences, Reactive Oxygen Species, Copper, Oxidative stress
Abstract: International audience; AIM: It has been convincingly shown that oxidative stress and toxicity by deregulated metals, such as copper (Cu), are tightly linked to the development of pre-eclampsia and intrauterine growth retardation (IUGR), the most threatening pathologies of human pregnancy. However, mechanisms implemented to control these effects are far from being understood. Among proteins that bind Cu and insure cellular protection against oxidative stress is the cellular prion protein (PrP(C)), a glycosyl phosphatidyl inositol-anchored glycoprotein, which we reported to be highly expressed in human placenta. Herein, we investigated the pathophysiological role of PrP(C) in Cu and oxidative stress homeostasis in vitro using human placenta and trophoblast cells, and in vivo using three strains of mice (C57Bl6, PrP(C) knockout mice [PrP(-/-)], and PrP(C) overexpressing mice [Tga20]). RESULTS: At the cellular level, PrP(C) protection against oxidative stress was established in multiple angiogenic processes: proliferation, migration, and tube-like organization. For the animal models, lack (PrP(-/-)) or overexpression (Tga20) of PrP(C) in gravid mice caused severe IUGR that was correlated with a decrease in litter size, changes in Cu homeostasis, increase in oxidative stress response, development of hypoxic environment, failure in placental function, and maintenance of growth defects of the offspring even 7.5 months after delivery. INNOVATION: PrP(C) could serve as a marker for the idiopathic IUGR disease. CONCLUSION: These findings demonstrate the stress-protective role of PrP(C) during development, and propose PrP(C) dysregulation as a novel causative element of IUGR.
Published: 2013

33. Sustained Endocrine Gland–Derived Vascular Endothelial Growth Factor Levels Beyond the First Trimester of Pregnancy Display Phenotypic and Functional Changes Associated With the Pathogenesis of Pregnancy-Induced Hypertension

Author: Mohamed Benharouga, Nadia Alfaidy, Aude Salomon, Vanessa Garnier, Jean-Jacques Feige, Pascale Hoffmann, Frederic Sergent, Sophie Brouillet, Padma Murthi, Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratoire d’Aide à la Procréation, Département de Génétique et Procréation (CECOS), Hôpital Couple Enfant de Grenoble-CHU de Grenoble, Department of Obstetrics and Gynaecology, University Hospital of Grenoble, La Tronche, France, Hudson Institute of Medical Research [Clayton], Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])
Subjects: 0301 basic medicine, Gestational hypertension, Placenta, Intrauterine growth restriction, 030204 cardiovascular system & hematology, Receptors, G-Protein-Coupled, Mice, Random Allocation, chemistry.chemical_compound, 0302 clinical medicine, Pregnancy, reproductive and urinary physiology, pregnancy-induced hypertension, Biopsy, Needle, Immunohistochemistry, 3. Good health, Vascular endothelial growth factor, Phenotype, medicine.anatomical_structure, embryonic structures, Female, medicine.medical_specialty, hypertension, endocrine gland-derived endothelial growth factor, Blotting, Western, Mice, Inbred Strains, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Real-Time Polymerase Chain Reaction, Sensitivity and Specificity, Preeclampsia, preeclampsia, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Internal Medicine, medicine, Animals, prokineticin 1, Eclampsia, business.industry, Trophoblast, Hypertension, Pregnancy-Induced, medicine.disease, Disease Models, Animal, Pregnancy Trimester, First, 030104 developmental biology, Endocrinology, chemistry, Pregnancy, Animal, Vascular Endothelial Growth Factor, Endocrine-Gland-Derived, business
Abstract: International audience; Pregnancy-induced hypertension diseases are classified as gestational hypertension, preeclampsia, or eclampsia. The mechanisms of their development and prediction are still to be discovered. Endocrine gland–derived vascular endothelial growth factor (EG-VEGF) is an angiogenic factor secreted by the placenta during the first trimester of human pregnancy that was shown to control trophoblast invasion, to be upregulated by hypoxia, and to be abnormally elevated in pathological pregnancies complicated with preeclampsia and intrauterine growth restriction. These findings suggested that sustaining EG-VEGF levels beyond the first trimester of pregnancy may contribute to pregnancy-induced hypertension. To test this hypothesis, osmotic minipumps delivering EG-VEGF were implanted subcutaneously into gravid OF1 (Oncins France 1) mice on day 11.5 post coitus, which is equivalent to the end of the first trimester of human pregnancy. Mice were euthanized at 15.5 and 18.5 days post coitus to assess (1) litter size, placental, and fetal weights; (2) placental histology and function; (3) maternal blood pressure; (4) renal histology and function; and (5) circulating soluble fms-like tyrosine kinase 1 and soluble endoglin. Increased EG-VEGF levels caused significant defects in placental organization and function. Both increased hypoxia and decreased trophoblast invasion were observed. Treated mice had elevated circulating soluble fms-like tyrosine kinase 1 and soluble endoglin and developed gestational hypertension with dysregulated maternal kidney function. EG-VEGF effect on the kidney function was secondary to its effects on the placenta as similarly treated male mice had normal kidney functions. Altogether, these data provide a strong evidence to confirm that sustained EG-VEGF beyond the first trimester of pregnancy contributes to the development of pregnancy-induced hypertension.
Published: 2016

34. Involvement of the heterodimeric interface region of the nucleotide binding domain-2 (NBD2) in the CFTR quaternary structure and membrane stability

Author: Klaus Ernst Ludwig Scheckenbach, Mohamed Benharouga, Marc Chanson, Sylvain Chauvet, Nadia Alfaidy, Julien Micoud, Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Geneva University Hospital (HUG), laboratory of clinical investigation III, University of Geneva [Switzerland], Biologie du Cancer et de l'Infection (BCI ), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université de Genève = University of Geneva (UNIGE), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG)
Subjects: congenital, hereditary, and neonatal diseases and abnormalities, Cystic Fibrosis Transmembrane Conductance Regulator, ATP-binding cassette transporter, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Cystic fibrosis, Protein–protein interaction, law.invention, Cell Line, law, Cricetinae, Cystic Fibrosis Transmembrane Conductance Regulator/chemistry/genetics/metabolism, Animals, Humans, Quaternary structure, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Cell Membrane/chemistry/genetics/metabolism, CFTR, Protein Structure, Quaternary, Membrane stability, Molecular Biology, NBD2, ddc:618, Protein Stability, Cell Membrane, Cell Biology, Cystic fibrosis transmembrane conductance regulator, Protein Structure, Tertiary, Transmembrane domain, Biochemistry, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Cyclic nucleotide-binding domain, Chloride channel, Recombinant DNA, biology.protein, Biophysics, Protein quaternary structure, Dimerization
Abstract: International audience; The cystic fibrosis transmembrane conductance regulator (CFTR) is the only member of the ATP-binding cassette (ABC) superfamily that functions as a chloride channel. The predicted structure of CFTR protein contains two membrane-spanning domains (MSDs), each followed by a nucleotide binding domain (NBD1 and NBD2). The opening of the Cl− channel is directly linked to ATP-driven tight dimerization of CFTR's NBD1 and NBD2 domains. The presence of a heterodimeric interfaces (HI) region in NBD1 and NBD2 generated a head to tail orientation necessary for channel activity. This process was also suggested to promote important conformational changes in the associated transmembrane domains of CFTR, which may impact the CFTR plasma membrane stability. To better understand the role of the individual HI region in this process, we generated recombinant CFTR protein with suppressed HI-NBD1 and HI-NBD2. Our results indicate that HI-NBD2 deletion leads to the loss of the dimerization profile of CFTR that affect its plasma membrane stability. We conclude that, in addition to its role in Cl− transport, HI-NBD2 domain confers membrane stability of CFTR by consolidating its quaternary structure through interactions with HI-NBD1 region.
Published: 2015

35. Revisiting the role of hCG: new regulation of the angiogenic factor EG-VEGF and its receptors

Author: Mohamed Benharouga, Frederic Sergent, Sylvain Chauvet, Jean-Jacques Feige, Sophie Brouillet, Pascale Hoffmann, S. Chamboredon, Nadia Alfaidy, Aude Salomon, Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Département de Gynécologie, Obstétrique et Médecine de la Reproduction, CHU Grenoble, Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), and Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG)
Subjects: Placenta, Gene Expression, Syncytiotrophoblasts, Chorionic Gonadotropin, Receptors, G-Protein-Coupled, chemistry.chemical_compound, 0302 clinical medicine, Pregnancy, Receptor, Cells, Cultured, reproductive and urinary physiology, 0303 health sciences, Receptors, LH, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Prokineticin, Trophoblasts, Vascular endothelial growth factor, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Molecular Medicine, Female, endocrine system, medicine.medical_specialty, Receptors, Peptide, Molecular Sequence Data, hCG, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, In Vitro Techniques, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Biology, Models, Biological, 03 medical and health sciences, Cellular and Molecular Neuroscience, Internal medicine, medicine, Humans, RNA, Messenger, EG-VEGF, Molecular Biology, DNA Primers, 030304 developmental biology, Pharmacology, Base Sequence, Prokineticin receptor 2, Trophoblast, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, Cell Biology, Prokineticin receptor 1, Placentation, Pregnancy Trimester, First, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Endocrinology, chemistry, Vascular Endothelial Growth Factor, Endocrine-Gland-Derived
Abstract: Endocrine gland-derived vascular endothelial growth factor (EG-VEGF) is an angiogenic factor reported to be specific for endocrine tissues, including the placenta. Its biological activity is mediated via two G protein-coupled receptors, prokineticin receptor 1 (PROKR1) and prokineticin receptor 2 (PROKR2). We have recently shown that (i) EG-VEGF expression peaks between the 8th and 11th weeks of gestation, (ii) its mRNA and protein levels are up-regulated by hypoxia, (iii) EG-VEGF is a negative regulator of trophoblast invasion and (iv) its circulating levels are increased in preeclampsia (PE), the most threatening pathology of pregnancy. Here, we investigated the regulation of the expression of EG-VEGF and its receptors by hCG, a key pregnancy hormone that is also deregulated in PE. During the first trimester of pregnancy, hCG and EG-VEGF exhibit the same pattern of expression, suggesting that EG-VEGF is potentially regulated by hCG. Both placental explants (PEX) and primary cultures of trophoblasts from the first trimester of pregnancy were used to investigate this hypothesis. Our results show that (i) LHCGR, the hCG receptor, is expressed both in cyto- and syncytiotrophoblasts, (ii) hCG increases EG-VEGF, PROKR1 and PROKR2 mRNA and protein expression in a dose- and time-dependent manner, (iii) hCG increases the release of EG-VEGF from PEX conditioned media, (iv) hCG effects are transcriptional and post-transcriptional and (v) the hCG effects are mediated by cAMP via cAMP response elements present in the EG-VEGF promoter region. Altogether, these results demonstrate a new role for hCG in the regulation of EG-VEGF and its receptors, an emerging regulatory system in placental development.
Published: 2011

36. Characterization of the role of NLRP7 protein in normal and tumor pregnancies: Case of Choriocarcinoma

Author: Nadia Alfaidy, R. Abi Nahed, Touria Aboussaouira, D. Reynaud, Mohamed Benharouga, and Wael Traboulsi
Subjects: 0301 basic medicine, 030219 obstetrics & reproductive medicine, Cell growth, Endocrinology, Diabetes and Metabolism, Choriocarcinoma, Trophoblast, General Medicine, Biology, Trophoblast cell, Hypoxia (medical), medicine.disease, female genital diseases and pregnancy complications, NLRP7, Metastasis, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Endocrinology, medicine.anatomical_structure, embryonic structures, medicine, Cancer research, Immunohistochemistry, medicine.symptom, reproductive and urinary physiology
Abstract: Choriocarcinoma is a veritable placental cancer that develops upon abnormal pregnancies named Hydatidiform Moles (HMs). Choriocarcinoma can metastasis in multiple maternal organs, such as lungs and the brain. Recent studies established an association between recurrent HMs and mutations in Nlrp7 gene. NLRP7 is a member of a family of proteins involved in inflammatory processes. Nevertheless, its role and biological functions remain to be elucidated. Using normal (HTR) and choriocarcinoma (JEG3) trophoblast cell lines, we characterized the role of NLRP7 in the control of key parameters of placental tumor development. Time lapse techniques were used to assess cell proliferation, migration and invasion. Using a distinctive cohort of normal, HM, and choriocarcinoma placental tissue and sera, we compared by immunohistochemistry and RT-qPCR the levels of NLRP7 expression. Sera was used to compare the inflammatory status in these cohorts. The in vitro study, demonstrated that NLRP7 is overexpressed in tumor cell lines and that its expression is up-regulated by hypoxia and b-hCG, two parameters that are associated to choriocarcinoma progression. Using siRNA strategy, we demonstrated that NLRP7 controls trophoblast proliferation, migration and invasion in 2D and 3D culture systems. The clinical study, demonstrated that NLRP7 protein was highly expressed in placentas collected from HM, and choriocarcinoma patients. Analysis of the inflammatory status of these cohorts showed strong deregulations in key circulating cytokines. Altogether our results demonstrate that NLRP7 controls key parameters of tumor placental development and bring new insights into the mechanisms that are associated to choriocarcinoma progression.
Published: 2018

37. Human cellular prion protein hPrPC is sorted to the apical membrane of epithelial cells

Author: Julien Micoud, B. De Keukeleire, Delphine Lechardeur, S. Donadio, Mohamed Benharouga, Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre National de la Recherche Scientifique (CNRS), Université Joseph Fourier - Grenoble 1 (UJF), UR 0888 Bactéries Lactiques et Pathogènes Opportunistes, Institut National de la Recherche Agronomique (INRA), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), and Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG)
Subjects: Gene isoform, [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], animal diseases, Biophysics, Hemagglutinin (influenza), Endogeny, Scrapie, CHO Cells, Biochemistry, Green fluorescent protein, 03 medical and health sciences, Cricetulus, Dogs, 0302 clinical medicine, Cricetinae, mental disorders, Animals, Humans, PrPC Proteins, Molecular Biology, 030304 developmental biology, 0303 health sciences, Gastrointestinal tract, biology, Cell Polarity, Epithelial Cells, Cell Biology, Apical membrane, Virology, Intestinal epithelium, nervous system diseases, 3. Good health, Cell biology, Caco-2 Cells/metabolism, PrPC Proteins/biosynthesis/*metabolism, Protein Transport, biology.protein, Caco-2 Cells, Epithelial Cells/*metabolism/*ultrastructure, 030217 neurology & neurosurgery
Abstract: Propagation of the scrapie isoform of the prion protein (PrP(Sc)) depends on the expression of endogenous cellular prion (PrP(C)). During oral infection, PrP(Sc) propagates, by conversion of the PrP(C) to PrP(Sc), from the gastrointestinal tract to the nervous system. Intestinal epithelium could serve as the primary site for PrP(C) conversion. To investigate PrP(C) sorting in epithelia cells, we have generated both a green fluorescent protein (EGFP) or hemagglutinin (HA) tagged human PrP(C) (hPrP(C)). Combined molecular, biochemical, and single living polarized cell imaging characterizations suggest that hPrP(C) is selectively targeted to the apical side of Madin-Darby canine kidney (MDCKII) and of intestinal epithelia (Caco2) cells.
Published: 2007

38. EG-VEGF, BV8, and their receptor expression in human bronchi and their modification in cystic fibrosis: Impact of CFTR mutation (delF508)

Author: Mohamed Benharouga, Wael Traboulsi, Laura Thevenon, Nadia Alfaidy, Boubou Camara, Sylvain Chauvet, Amal Kouadri, Jean-Jacques Feige, Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Biologie du Cancer et de l'Infection (BCI ), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Ressources et de Compétences de la Mucoviscidose, hôpital Sud, Centre hospitalier universitaire de Grenoble (CHU de Grenoble), CHU Grenoble, Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG)
Subjects: Male, Pathology, Cystic Fibrosis, Physiology, Angiogenesis, Receptor expression, Gene Expression, Cystic fibrosis, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Receptors, G-Protein-Coupled, chemistry.chemical_compound, 0302 clinical medicine, Lung, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Sequence Deletion, 0303 health sciences, Middle Aged, Cystic fibrosis transmembrane conductance regulator, Vascular endothelial growth factor, medicine.anatomical_structure, prokineticin receptors, Female, Endocrine gland, Pulmonary and Respiratory Medicine, Adult, medicine.medical_specialty, Receptors, Peptide, Biology, Gastrointestinal Hormones, 03 medical and health sciences, Young Adult, Chlorides, Physiology (medical), Cell Line, Tumor, medicine, Homologous chromosome, Humans, Calcium Signaling, BV8/endocrine gland vascular endothelial growth factor, 030304 developmental biology, Aged, cystic fibrosis transmembrane conductance regulator, Neuropeptides, lung angiogenesis, Epithelial Cells, Cell Biology, medicine.disease, 030228 respiratory system, chemistry, Case-Control Studies, biology.protein, Vascular Endothelial Growth Factor, Endocrine-Gland-Derived, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Enhanced lung angiogenesis has been reported in cystic fibrosis (CF). Recently, two highly homologous ligands, endocrine gland vascular endothelial growth factor (EG-VEGF) and mammalian Bv8, have been described as new angiogenic factors. Both ligands bind and activate two closely related G protein-coupled receptors, the prokineticin receptor (PROKR) 1 and 2. Yet, the expression, regulation, and potential role of EG-VEGF, BV8, and their receptors in normal and CF lung are still unknown. The expression of the receptors and their ligands was examined using molecular, biochemical, and immunocytochemistry analyses in lungs obtained from CF patients vs. control and in normal and CF bronchial epithelial cells. Cystic fibrosis transmembrane conductance regulator (CFTR) activity was evaluated in relation to both ligands, and concentrations of EG-VEGF were measured by ELISA. At the mRNA level, EG-VEGF, BV8, and PROKR2 gene expression was, respectively, approximately five, four, and two times higher in CF lungs compared with the controls. At the cellular level, both the ligands and their receptors showed elevated expressions in the CF condition. Similar results were observed at the protein level. The EG-VEGF secretion was apical and was approximately two times higher in CF compared with the normal epithelial cells. This secretion was increased following the inhibition of CFTR chloride channel activity. More importantly, EG-VEGF and BV8 increased the intracellular concentration of Ca2+ and cAMP and stimulated CFTR-chloride channel activity. Altogether, these data suggest local roles for epithelial BV8 and EG-VEGF in the CF airway peribronchial vascular remodeling and highlighted the role of CFTR activity in both ligand biosynthesis and secretion.
Published: 2015

39. The Na+/K+-ATPase and the amyloid-beta peptide aβ1-40 control the cellular distribution, abundance and activity of TRPC6 channels

Author: Mohamed Benharouga, Alexandre Bouron, Sylvain Chauvet, Michel Jadot, Mireille Chevallet, Peter Faller, Addis Abebe, Marielle Boonen, Louis Jarvis, Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Department of Physiological Chemistry, Facultés Universitaires Notre Dame de la Paix (FUNDP), Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), and Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Amyloid beta, TRPC6, Peptide, Aβ peptides, Ouabain, chemistry.chemical_compound, Mice, Aβpeptides, BAPTA, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, TRPC6 Cation Channel, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Calcium Signaling, Na+/K+-ATPase, Molecular Biology, TRPC Cation Channels, Neurons, chemistry.chemical_classification, Trafficking, Amyloid beta-Peptides, biology, Na/K pump, Depolarization, Cell Biology, Na/K, Peptide Fragments, Protein Transport, HEK293 Cells, Biochemistry, chemistry, pump, biology.protein, Biophysics, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Sodium-Potassium-Exchanging ATPase, Lysosomes, Veratridine, medicine.drug
Abstract: The Na(+)/K(+)-ATPase interacts with the non-selective cation channels TRPC6 but the functional consequences of this association are unknown. Experiments performed with HEK cells over-expressing TRPC6 channels showed that inhibiting the activity of the Na(+)/K(+)-ATPase with ouabain reduced the amount of TRPC6 proteins and depressed Ca(2+) entry through TRPC6. This effect, not mimicked by membrane depolarization with KCl, was abolished by sucrose and bafilomycin-A, and was partially sensitive to the intracellular Ca(2+) chelator BAPTA/AM. Biotinylation and subcellular fractionation experiments showed that ouabain caused a multifaceted redistribution of TRPC6 to the plasma membrane and to an endo/lysosomal compartment where they were degraded. The amyloid beta peptide Aβ(1-40), another inhibitor of the Na(+)/K(+)-ATPase, but not the shorter peptide Aβ1-16, reduced TRPC6 protein levels and depressed TRPC6-mediated responses. In cortical neurons from embryonic mice, ouabain, veratridine (an opener of voltage-gated Na(+) channel), and Aβ(1-40) reduced TRPC6-mediated Ca(2+) responses whereas Aβ(1-16) was ineffective. Furthermore, when Aβ(1-40) was co-added together with zinc acetate it could no longer control TRPC6 activity. Altogether, this work shows the existence of a functional coupling between the Na(+)/K(+)-ATPase and TRPC6. It also suggests that the abundance, distribution and activity of TRPC6 can be regulated by cardiotonic steroids like ouabain and the naturally occurring peptide Aβ(1-40) which underlines the pathophysiological significance of these processes.
Published: 2015

40. An EG-VEGF-dependent decrease in homeobox gene NKX3.1 contributes to cytotrophoblast dysfunction: a possible mechanism in human fetal growth restriction

Author: Nadia Alfaidy, Frédéric Goffin, Vassilis Tsatsaris, Jean-Jacques Feige, Carine Munaut, Anita Pratt, Bill Kalionis, Padma Murthi, Mohamed Benharouga, Anthony J. Borg, Sophie Brouillet, Thierry Fournier, Department of Obstetrics and Gynaecology [Melbourne], Melbourne Medical School [Melbourne], Faculty of Medicine, Dentistry and Health Sciences [Melbourne], University of Melbourne-University of Melbourne-Faculty of Medicine, Dentistry and Health Sciences [Melbourne], University of Melbourne-University of Melbourne, Department of Perinatal Medicine, Royal Women's Hospital, Monash University [Clayton], Department of Medicine, Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Pôle Couple-Enfant, Département de Génétique et Procréation, Laboratoire de Biologie des Tumeurs et du Développement), Université de Liège, La grossesse normale et pathologique: développement et fonctions du placenta et de l'utérus (UMR_S 767), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Maternité Port-Royal [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), PremUp Foundation, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Descartes - Paris 5 (UPD5)-CHI Créteil-Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7), Physiopathologie et Pharmacotoxicologie Placentaire Humaine (U1139), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Biologie des Métaux (BioMet), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Invasion mechanisms in angiogenesis and cancer (IMAC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), laboratory of clinical investigation III, University of Geneva [Switzerland], Department of Obstetrics and Gynaecology, University of Melbourne, Biologie du Cancer et de l'Infection ( BCI - UMR S1036 ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Grenoble Alpes ( UGA ), CHU de Grenoble, Hôpital Couple-Enfant, Département de Génétique et Procréation, La grossesse normale et pathologique: développement et fonctions du placenta et de l'utérus ( UMR_S 767 ), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement ( IFR71 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP], Laboratoire de Chimie et Biologie des Métaux ( LCBM - UMR 5249 ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), Institut de Recherche pour le Développement ( IRD ) -Université Paris-Sud - Paris 11 ( UP11 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Diderot - Paris 7 ( UPD7 ) -CHI Créteil-Université Paris Descartes - Paris 5 ( UPD5 ) -Sorbonne Universités-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Physiopathologie et Pharmacotoxicologie Placentaire Humaine ( U1139 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-CHI Créteil-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-CHI Créteil-Université Paris Descartes - Paris 5 (UPD5)-Sorbonne Universités-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: MESH: Protein Structure, Quaternary, MESH: Cricetinae, Placental insufficiency, Biology, Cystic fibrosis, Andrology, MESH: Protein Structure, Tertiary, chemistry.chemical_compound, Syncytiotrophoblast, MESH: Protein Stability, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, medicine, Quaternary structure, MESH: Animals, CFTR, Membrane stability, [ SDV.MHEP.GEO ] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, NBD2, Molecular Biology, Gene, Genetics (clinical), MESH: Cystic Fibrosis Transmembrane Conductance Regulator, Messenger RNA, MESH: Humans, Cytotrophoblast, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, Trophoblast, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, Articles, medicine.disease, Molecular biology, MESH: Cell Line, Vascular endothelial growth factor, [ SDV.BDLR ] Life Sciences [q-bio]/Reproductive Biology, medicine.anatomical_structure, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, chemistry, [ SDV.BDD.EO ] Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, embryonic structures, Molecular Medicine, Homeobox, Dimerization, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, MESH: Cell Membrane
Abstract: International audience; Idiopathic fetal growth restriction (FGR) is frequently associated with placental insufficiency. Previous reports have provided evidence that endocrine gland-derived vascular endothelial growth factor (EG-VEGF), a placental secreted protein, is expressed during the first trimester of pregnancy, controls both trophoblast proliferation and invasion, and its increased expression is associated with human FGR. In this study, we hypothesize that EG-VEGF-dependent changes in placental homeobox gene expressions contribute to trophoblast dysfunction in idiopathic FGR. The changes in EG-VEGF-dependent homeobox gene expressions were determined using a homeobox gene cDNA array on placental explants of 8-12 wks gestation after stimulation with EG-VEGF in vitro for 24 h. The homeobox gene array identified a greater-than-five-fold increase in HOXA9, HOXC8, HOXC10, HOXD1, HOXD8, HOXD9 and HOXD11, while NKX 3.1 showed a greater-than-two-fold decrease in mRNA expression compared with untreated controls. Homeobox gene NKX3.1 was selected as a candidate because it is a downstream target of EG-VEGF and its expression and functional roles are largely unknown in control and idiopathic FGR-affected placentae. Real-time PCR and immunoblotting showed a significant decrease in NKX3.1 mRNA and protein levels, respectively, in placentae from FGR compared with control pregnancies. Gene inactivation in vitro using short-interference RNA specific for NKX3.1 demonstrated an increase in BeWo cell differentiation and a decrease in HTR-8/SVneo proliferation. We conclude that the decreased expression of homeobox gene NKX3.1 downstream of EG-VEGF may contribute to the trophoblast dysfunction associated with idiopathic FGR pregnancies.
Published: 2015

41. Misfolding diverts CFTR from recycling to degradation

Author: Kristi G. Bache, Blake C. Papsin, Harald Stenmark, Francesca Pampinella, Mohamed Benharouga, Gergely L. Lukacs, Noa Zerangue, Jeffrey So, Csilla Nemes, Manu Sharma, and Kai Du
Subjects: Protein Folding, Protein Conformation, Endosome, Recombinant Fusion Proteins, Cystic Fibrosis Transmembrane Conductance Regulator, Golgi Apparatus, Endosomes, Endocytosis, Article, Cell Line, Cell membrane, 03 medical and health sciences, Ubiquitin, recycling, sorting, mutation, endocytosis, ubiquitin receptors, Cricetinae, medicine, Animals, Humans, TSG101, Ubiquitins, 030304 developmental biology, 0303 health sciences, biology, Cell Membrane, 030302 biochemistry & molecular biology, Epithelial Cells, Cell Biology, Cystic fibrosis transmembrane conductance regulator, Transport protein, Cell biology, Protein Transport, medicine.anatomical_structure, Membrane protein, biology.protein, Lysosomes
Abstract: To investigate the degradation mechanism of misfolded membrane proteins from the cell surface, we used mutant cystic fibrosis transmembrane conductance regulators (CFTRs) exhibiting conformational defects in post-Golgi compartments. Here, we show that the folding state of CFTR determines the post-endocytic trafficking of the channel. Although native CFTR recycled from early endosomes back to the cell surface, misfolding prevented recycling and facilitated lysosomal targeting by promoting the ubiquitination of the channel. Rescuing the folding defect or down-regulating the E1 ubiquitin (Ub)-activating enzyme stabilized the mutant CFTR without interfering with its internalization. These observations with the preferential association of mutant CFTRs with Hrs, STAM-2, TSG101, hVps25, and hVps32, components of the Ub-dependent endosomal sorting machinery, establish a functional link between Ub modification and lysosomal degradation of misfolded CFTR from the cell surface. Our data provide evidence for a novel cellular mechanism of CF pathogenesis and suggest a paradigm for the quality control of plasma membrane proteins involving the coordinated function of ubiquitination and the Ub-dependent endosomal sorting machinery.
Published: 2004

42. NLRP7 inflammasome is activated in FGR pregnancies: Physiological and physio-pathological implications

Author: Nadia Alfaidy, Marie-Noëlle Dieudonné, Pascale Hoffmann, Mohamed Benharouga, Déborah Reynaud, Sophie Ndagijimana, Roland Abi Nahed, and Wael Traboulsi
Subjects: Reproductive Medicine, business.industry, Immunology, medicine, Obstetrics and Gynecology, Inflammasome, business, Pathological, NLRP7, Developmental Biology, medicine.drug
Published: 2017

43. Antagonism of EG-VEGF receptors is a novel targeted therapy for choriocarcinoma progression: in vitro, in vivo and in clinical studies

Author: Wael Traboulsi, Giafranco Balboni, Frederic Sergent, Mohamed Benharouga, Houssine Boufettal, Nadia Alfaidy, Sophie Brouillet, Qun-Yong Zhou, Pascale Hoffmann, Jean-Jacques Feige, and Touria Aboussaouira
Subjects: business.industry, medicine.medical_treatment, Choriocarcinoma, Obstetrics and Gynecology, Pharmacology, medicine.disease, Targeted therapy, Reproductive Medicine, Medicine, In vitro in vivo, Receptor, business, Antagonism, Developmental Biology
Published: 2017

44. Endocrine Gland-Derived Endothelial Growth Factor (EG-VEGF) Is a Potential Novel Regulator of Human Parturition1

Author: L. Blanchon, Sally Sabra, Mohamed Benharouga, Jean Guibourdenche, Frederic Sergent, Pascale Hoffmann, Jean-Jacques Feige, Aude Salomon, C. Dunand, Stephen J. Lye, Vincent Sapin, and Nadia Alfaidy
Subjects: Placental growth factor, medicine.medical_specialty, Pregnancy, Amnion, Growth factor, medicine.medical_treatment, Trophoblast, Cell Biology, General Medicine, Biology, medicine.disease, medicine.anatomical_structure, Endocrinology, Reproductive Medicine, Fetal membrane, Internal medicine, embryonic structures, medicine, Receptor, reproductive and urinary physiology, Endocrine gland
Abstract: EG-VEGF is an angiogenic factor that we identified as a new placental growth factor during human pregnancy. EG-VEGF is also expressed in the mouse fetal membrane (FM) by the end of gestation, suggesting a local role for this protein in the mechanism of parturition. However, injection of EG-VEGF to gravid mice did not induce labor, suggesting a different role for EG-VEGF in parturition. Here, we searched for its role in the FM in relation to human parturition. Human pregnant sera and total FM, chorion, and amnion were collected during the second and third trimesters from preterm no labor, term no labor, and term labor patients. Primary human chorion trophoblast and FM explants cultures were also used. We demonstrate that circulating EG-VEGF increased toward term and significantly decreased at the time of labor. EG-VEGF production was higher in the FM compared to placentas matched for gestational age. Within the FM, the chorion was the main source of EG-VEGF. EG-VEGF receptors, PROKR1 and PROKR2, were differentially expressed within the FM with increased expression toward term and an abrupt decrease with the onset of labor. In chorion trophoblast and FM explants collected from nonlaboring patients, EG-VEGF decreased metalloproteinase-2 and -9 activities and increased PGDH (prostaglandin-metabolizing enzyme) expression. Altogether these data demonstrate that EG-VEGF is a new cytokine that acts locally to ensure FM protection in late pregnancy. Its fine contribution to the initiation of human labor is exhibited by the abrupt decrease in its levels as well as a reduction in its receptors.
Published: 2014

45. The Multiple Roles of EG-VEGF/PROK1 in Normal and Pathological Placental Angiogenesis

Author: Sophie Brouillet, Touria Aboussaouira, Houssine Boufettal, Pascale Hoffmann, Mohamed Benharouga, Naïma Samouh, Nadia Alfaidy, Jean-Jacques Feige, Biologie du Cancer et de l'Infection (BCI ), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique médicale CHU Grenoble Hôpital Couple Enfant, CHU Grenoble, Ibn Rochd University Hospital, Faculté de Médecine et Pharmacie Casablanca, University King Hassan II-Aïn Chok, Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), and Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG)
Subjects: medicine.medical_specialty, Angiogenesis, Placenta, lcsh:Medicine, Neovascularization, Physiologic, Review Article, Biology, Bioinformatics, General Biochemistry, Genetics and Molecular Biology, Preeclampsia, Gastrointestinal Hormones, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Vasculogenesis, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Pregnancy, Internal medicine, medicine, Humans, 030304 developmental biology, 0303 health sciences, 030219 obstetrics & reproductive medicine, General Immunology and Microbiology, Neovascularization, Pathologic, lcsh:R, Placentation, General Medicine, medicine.disease, Prokineticin, Vascular endothelial growth factor, Endocrinology, medicine.anatomical_structure, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, chemistry, Female, Vascular Endothelial Growth Factor, Endocrine-Gland-Derived
Abstract: International audience; Placentation is associated with several steps of vascular adaptations throughout pregnancy. These vascular changes occur both on the maternal and fetal sides, consisting of maternal uterine spiral arteries remodeling and placental vasculogenesis and angiogenesis, respectively. Placental angiogenesis is a pivotal process for efficient fetomaternal exchanges and placental development. This process is finely controlled throughout pregnancy, and it involves ubiquitous and pregnancy-specific angiogenic factors. In the last decade, endocrine gland derived vascular endothelial growth factor (EG-VEGF), also called prokineticin 1 (PROK1), has emerged as specific placental angiogenic factor that controls many aspects of normal and pathological placental angiogenesis such as recurrent pregnancy loss (RPL), gestational trophoblastic diseases (GTD), fetal growth restriction (FGR), and preeclampsia (PE). This review recapitulates EG-VEGF mediated-angiogenesis within the placenta and at the fetomaternal interface and proposes that its deregulation might contribute to the pathogenesis of several placental diseases including FGR and PE. More importantly this paper argues for EG-VEGF clinical relevance as a potential biomarker of the onset of pregnancy pathologies and discusses its potential usefulness for future therapeutic directions.
Published: 2014

46. Characterization of the adverse effects of nicotine on placental development: in vivo and in vitro studies

Author: Nadia Alfaidy, Frederic Sergent, Aude Salomon, Jean-Jacques Feige, Vanessa Garnier, Alison C. Holloway, Mohamed Benharouga, Michael J. Soares, Catherine J. Nicholson, Sandeep Raha, Mc Master University, Hamilton, Ontario, Canada, Department of Obstetrics and Gynecology, Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), University of Kansas Medical Center [Lawrence], Institute for Reproductive Health and Regenerative Medicine, Department of Pediatrics, Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and University of Kansas Medical Center [Kansas City, KS, USA]
Subjects: Vascular Endothelial Growth Factor A, medicine.medical_specialty, Nicotine, Physiology, Endocrinology, Diabetes and Metabolism, Placenta, Biology, Cell Line, 03 medical and health sciences, endocrine gland-derived vascular endothelial growth factor, 0302 clinical medicine, In vivo, Pregnancy, Physiology (medical), Internal medicine, medicine, Basic Helix-Loop-Helix Transcription Factors, Animals, Rats, Wistar, Adverse effect, 030304 developmental biology, Cell Proliferation, 0303 health sciences, Fetus, Articles, In vitro, Placentation, 3. Good health, Rats, Trophoblasts, Endocrinology, Increased risk, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, In utero, Neonatal outcomes, matrix metalloproteinase 9, Female, nicotinic acetylcholine receptors, rat placentation, trophoblast invasion and differentiation, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, medicine.drug
Abstract: In utero exposure to nicotine is associated with increased risk of numerous adverse fetal and neonatal outcomes, which suggests that it acts directly to affect placental development and the establishment of the fetomaternal circulation (FC). This study used both in vivo [Wistar rats treated with 1 mg/kg nicotine from 2 wk prior to mating until gestational day (GD) 15] and in vitro (RCHO-1 cell line; treated with 10−9to 10−3M nicotine) models to examine the effects of nicotine on these pathways. At GD 15, control and treated placentas were examined for the impact of nicotine on 1) trophoblast invasion, proliferation, and degree of hypoxia, 2) labyrinth vascularization, 3) expression of key genes of placental development, and 4) expression of placental angiogenic factors. The RCHO-1 cell line was used to determine the direct effects of nicotine on trophoblast differentiation. Our in vivo experiments show that nicotine inhibits trophoblast interstitial invasion, increases placental hypoxia, downregulates labyrinth vascularization as well as key transcription factors Hand1 and GCM1, and decreases local and circulating EG-VEGF, a key placental angiogenic factor. The in vitro experiments confirmed the inhibitory effects of nicotine on the trophoblast migration, invasion, and differentiation processes and demonstrated that those effects are most likely due to a dysregulation in the expression of nicotine receptors and a decrease in MMP9 activity. Taken together, these data suggest that adverse effects of maternal smoking on pregnancy outcome are due in part to direct and endocrine effects of nicotine on the main processes of placental development and establishment of FC.
Published: 2014

47. Cooh-Terminal Truncations Promote Proteasome-Dependent Degradation of Mature Cystic Fibrosis Transmembrane Conductance Regulator from Post-Golgi Compartments

Author: Martin Haardt, Mohamed Benharouga, Norbert Kartner, and Gergely L. Lukacs
Subjects: Proteasome Endopeptidase Complex, Protein Folding, Glycosylation, Endosome, Cystic Fibrosis Transmembrane Conductance Regulator, Golgi Apparatus, Endosomes, ubiquitination, Cell Line, Frameshift mutation, cystic fibrosis, Cell membrane, Multienzyme Complexes, Cricetinae, medicine, Animals, Protease Inhibitors, Frameshift Mutation, Ubiquitins, Sequence Deletion, Brefeldin A, biology, Cell Membrane, Temperature, Cell Biology, Molecular biology, Peptide Fragments, Cystic fibrosis transmembrane conductance regulator, Transmembrane protein, Transport protein, Cell biology, Cysteine Endopeptidases, Kinetics, Protein Transport, medicine.anatomical_structure, Membrane protein, functional complementation, Codon, Terminator, Chloride channel, biology.protein, Thermodynamics, Original Article, structural destabilization, Lysosomes, Protein Processing, Post-Translational, lysosomal proteolysis
Abstract: Impaired biosynthetic processing of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR), a cAMP-regulated chloride channel, constitutes the most common cause of CF. Recently, we have identified a distinct category of mutation, caused by premature stop codons and frameshift mutations, which manifests in diminished expression of COOH-terminally truncated CFTR at the cell surface. Although the biosynthetic processing and plasma membrane targeting of truncated CFTRs are preserved, the turnover of the complex-glycosylated mutant is sixfold faster than its wild-type (wt) counterpart. Destabilization of the truncated CFTR coincides with its enhanced susceptibility to proteasome-dependent degradation from post-Golgi compartments globally, and the plasma membrane specifically, determined by pulse–chase analysis in conjunction with cell surface biotinylation. Proteolytic cleavage of the full-length complex-glycosylated wt and degradation intermediates derived from both T70 and wt CFTR requires endolysosomal proteases. The enhanced protease sensitivity in vitro and the decreased thermostability of the complex-glycosylated T70 CFTR in vivo suggest that structural destabilization may account for the increased proteasome susceptibility and the short residence time at the cell surface. These in turn are responsible, at least in part, for the phenotypic manifestation of CF. We propose that the proteasome-ubiquitin pathway may be involved in the peripheral quality control of other, partially unfolded membrane proteins as well.
Published: 2001

48. C-terminal Truncations Destabilize the Cystic Fibrosis Transmembrane Conductance Regulator without Impairing Its Biogenesis

Author: Norbert Kartner, Martin Haardt, Delphine Lechardeur, Mohamed Benharouga, and Gergely L. Lukacs
Subjects: congenital, hereditary, and neonatal diseases and abnormalities, Mutation, Endoplasmic reticulum, Wild type, Heterozygote advantage, Cell Biology, Biology, medicine.disease, medicine.disease_cause, Biochemistry, Cystic fibrosis, Cystic fibrosis transmembrane conductance regulator, Cell biology, Frameshift mutation, medicine, Chloride channel, biology.protein, Molecular Biology
Abstract: Defective cAMP-stimulated chloride conductance of the plasma membrane of epithelial cell is the hallmark of cystic fibrosis (CF) and results from mutations in the cystic fibrosis transmembrane conductance regulator, CFTR. In the majority of CF patients, mutations in the CFTR lead to its misfolding and premature degradation at the endoplasmic reticulum (ER). Other mutations impair the cAMP-dependent activation or the ion conductance of CFTR chloride channel. In the present work we identify a novel mechanism leading to reduced expression of CFTR at the cell surface, caused by C-terminal truncations. The phenotype of C-terminally truncated CFTR, representing naturally occurring premature termination and frameshift mutations, were examined in transient and stable heterologous expression systems. Whereas the biosynthesis, processing, and macroscopic chloride channel function of truncated CFTRs are essentially normal, the degradation rate of the mature, complex-glycosylated form is 5- to 6-fold faster than the wild type CFTR. These experiments suggest that the C terminus has a central role in maintaining the metabolic stability of the complex-glycosylated CFTR following its exit from the ER and provide a plausible explanation for the severe phenotype of CF patients harboring C-terminal truncations.
Published: 1999

49. EG-VEGF controls placental growth and survival in normal and pathological pregnancies: case of fetal growth restriction (FGR)

Author: Jean-Jacques Feige, Nadia Alfaidy, Mbarka Dakouane-Giudicelli, Aude Salomon, Pascale Hoffmann, Marie-Noëlle Dieudonné, Sophie Brouillet, Sandrine Barbaux, P. De Mazancourt, Frederic Sergent, Mohamed Benharouga, Daniel Vaiman, P. Rozenberg, Padma Murthi, Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Department of Perinatal Medicine, Pregnancy Research Centre, The Royal Women's Hospital, Department of Obstetrics and Gynaecology [Melbourne], Melbourne Medical School [Melbourne], Faculty of Medicine, Dentistry and Health Sciences [Melbourne], University of Melbourne-University of Melbourne-Faculty of Medicine, Dentistry and Health Sciences [Melbourne], University of Melbourne-University of Melbourne, Département de Gynécologie, Obstétrique et Médecine de la Reproduction, CHU Grenoble, Unité de pathologie cellulaire et génétique (UPCG), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Biologie du Cancer et de l'Infection ( BCI - UMR S1036 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Grenoble Alpes ( UGA ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Department of Obstetrics and Gynaecology, University of Melbourne, Unité de pathologie cellulaire et génétique ( UPCG ), Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Chimie et Biologie des Métaux ( LCBM - UMR 5249 ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG)
Subjects: Placental growth factor, HUMAN TROPHOBLAST, Placenta, Giant Cells, Receptors, G-Protein-Coupled, Human chorionic gonadotropin, UMBILICAL ARTERY, 0302 clinical medicine, Pregnancy, MOLECULAR CHARACTERIZATION, Receptor, [ SDV.MHEP.GEO ] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Cells, Cultured, IN-VITRO DIFFERENTIATION, 0303 health sciences, VILLOUS CYTOTROPHOBLAST DIFFERENTIATION, Fetal Growth Retardation, 030219 obstetrics & reproductive medicine, FGR, Prokineticin, Cell Hypoxia, Recombinant Proteins, Trophoblasts, Up-Regulation, 3. Good health, HOMEOBOX GENE HLX1, [ SDV.BDLR ] Life Sciences [q-bio]/Reproductive Biology, medicine.anatomical_structure, Molecular Medicine, Female, medicine.medical_specialty, Receptors, Peptide, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, CELL-PROLIFERATION, 03 medical and health sciences, Cellular and Molecular Neuroscience, HUMAN CHORIONIC-GONADOTROPIN, Internal medicine, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, RNA, Messenger, EG-VEGF, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, Cell Proliferation, 030304 developmental biology, Homeodomain Proteins, Pharmacology, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, INTRAUTERINE GROWTH, Trophoblast, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, Cell Biology, Prokineticin receptor 1, medicine.disease, ENDOTHELIAL-CELLS, Placentation, Pregnancy Trimester, First, Endocrinology, Vascular Endothelial Growth Factor, Endocrine-Gland-Derived, Angiogenesis, Transcription Factors
Abstract: International audience; Identifiable causes of fetal growth restriction (FGR) account for 30 % of cases, but the remainders are idiopathic and are frequently associated with placental dysfunction. We have shown that the angiogenic factor endocrine gland-derived VEGF (EG-VEGF) and its receptors, prokineticin receptor 1 (PROKR1) and 2, (1) are abundantly expressed in human placenta, (2) are up-regulated by hypoxia, (3) control trophoblast invasion, and that EG-VEGF circulating levels are the highest during the first trimester of pregnancy, the period of important placental growth. These findings suggest that EG-VEGF/PROKR1 and 2 might be involved in normal and FGR placental development. To test this hypothesis, we used placental explants, primary trophoblast cultures, and placental and serum samples collected from FGR and age-matched control women. Our results show that (1) EG-VEGF increases trophoblast proliferation ([3H]-thymidine incorporation and Ki67-staining) via the homeobox-gene, HLX (2) the proliferative effect involves PROKR1 but not PROKR2, (3) EG-VEGF does not affect syncytium formation (measurement of syncytin 1 and 2 and β hCG production) (4) EG-VEGF increases the vascularization of the placental villi and insures their survival, (5) EG-VEGF, PROKR1, and PROKR2 mRNA and protein levels are significantly elevated in FGR placentas, and (6) EG-VEGF circulating levels are significantly higher in FGR patients. Altogether, our results identify EG-VEGF as a new placental growth factor acting during the first trimester of pregnancy, established its mechanism of action, and provide evidence for its deregulation in FGR. We propose that EG-VEGF/PROKR1 and 2 increases occur in FGR as a compensatory mechanism to insure proper pregnancy progress.
Published: 2013

50. Molecular Characterization of EG-VEGF-mediated Angiogenesis: Differential Effects on Microvascular and Macrovascular Endothelial Cells

Author: Sophie Brouillet, Mohamed Benharouga, Jean-Patrick Schaal, Jean-Jacques Feige, Nadia Alfaidy, Aude Salomon, Pascale Hoffmann, Angiogenèse hormono-regulée et angiogenèse tumorale (LAPV), Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Gynécologie, Obstétrique et Médecine de la Reproduction, CHU Grenoble, Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)
Subjects: Vascular Endothelial Growth Factor A, Cell Membrane Permeability, Angiogenesis, Placenta, Gene Expression, PROTEIN, Apoptosis, Receptors, G-Protein-Coupled, Umbilical Cord, chemistry.chemical_compound, 0302 clinical medicine, Cell Movement, Pregnancy, HETEROGENEITY, Receptor, Cells, Cultured, 0303 health sciences, Reverse Transcriptase Polymerase Chain Reaction, Articles, Immunohistochemistry, Prokineticin, Cell biology, Platelet Endothelial Cell Adhesion Molecule-1, Endothelial stem cell, Vascular endothelial growth factor, Vascular endothelial growth factor A, medicine.anatomical_structure, PROKINETICIN RECEPTOR-1, 030220 oncology & carcinogenesis, Paracellular transport, Female, RNA Interference, Mitogen-Activated Protein Kinases, EXPRESSION, Cell Physiology, GROWTH-FACTOR, Receptors, Peptide, Cell Survival, Blotting, Western, Neovascularization, Physiologic, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, 03 medical and health sciences, FACTOR/PROKINETICIN-1, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, Molecular Biology, Cell Proliferation, 030304 developmental biology, EARLY HUMAN PLACENTA, IDENTIFICATION, Endothelial Cells, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, Cell Biology, Molecular biology, chemistry, VASCULOGENESIS, Vascular Endothelial Growth Factor, Endocrine-Gland-Derived, EARLY-PREGNANCY
Abstract: The existence of organ-specific angiogenic factor has recently received confirmation when EG-VEGF was identified. Here we characterized its angiogenic processes in endothelial cells (ECs), compared its effects in micro- and macrovascular ECs, and differentiated the effects mediated by its two G-protein–coupled receptors within the same cell type., Endocrine gland derived vascular endothelial growth factor (EG-VEGF) also called prokineticin (PK1), has been identified and linked to several biological processes including angiogenesis. EG-VEGF is abundantly expressed in the highest vascularized organ, the human placenta. Here we characterized its angiogenic effect using different experimental procedures. Immunohistochemistry was used to localize EG-VEGF receptors (PROKR1 and PROKR2) in placental and umbilical cord tissue. Primary microvascular placental endothelial cell (HPEC) and umbilical vein-derived macrovascular EC (HUVEC) were used to assess its effects on proliferation, migration, cell survival, pseudovascular organization, spheroid sprouting, permeability and paracellular transport. siRNA and neutralizing antibody strategies were used to differentiate PROKR1- from PROKR2-mediated effects. Our results show that 1) HPEC and HUVEC express both types of receptors 2) EG-VEGF stimulates HPEC's proliferation, migration and survival, but increases only survival in HUVECs. and 3) EG-VEGF was more potent than VEGF in stimulating HPEC sprout formation, pseudovascular organization, and it significantly increases HPEC permeability and paracellular transport. More importantly, we demonstrated that PROKR1 mediates EG-VEGF angiogenic effects, whereas PROKR2 mediates cellular permeability. Altogether, these data characterized angiogenic processes mediated by EG-VEGF, depicted a new angiogenic factor in the placenta, and suggest a novel view of the regulation of angiogenesis in placental pathologies.
Published: 2010

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