Search

Your search keyword '"Rana Zahreddine"' showing total 7 results
Start Over Author "Rana Zahreddine" Topic animals
7 results on '"Rana Zahreddine"'

1. A historical view of estrogen effect on arterial endothelial healing: From animal models to medical implication

Author

Coralie Fontaine, Melissa Buscato, Morgane Davezac, Jean-François Arnal, Rana Zahreddine, Natalia F. Smirnova, Marine Adlanmerini, Daniel Henrion, Muriel Laffargue, and Françoise Lenfant

Subjects
Genetically modified mouse, Cell type, Estradiol, Endothelium, business.industry, medicine.drug_class, Estrogen receptor, Estrogens, Atherosclerosis, Cell biology, Endothelial stem cell, Mice, medicine.anatomical_structure, Selective estrogen receptor modulator, Estrogen, Models, Animal, Animals, Medicine, Endothelium, Vascular, Cardiology and Cardiovascular Medicine, business, Receptor
Abstract

Endothelial barrier integrity is required for maintaining vascular homeostasis and fluid balance between the circulation and surrounding tissues. In contrast, abnormalities of endothelial cell function and loss of the integrity of the endothelial monolayer constitute a key step in the onset of atherosclerosis. Endothelial erosion is directly responsible for thrombus formation and cardiovascular events in about one-third of the cases of acute coronary syndromes. Thus, after endothelial injury, the vascular repair process is crucial to restore endothelial junctions and rehabilitate a semipermeable barrier, preventing the development of vascular diseases. Endothelial healing can be modulated by several factors. In particular, 17β-estradiol (E2), the main estrogen, improves endothelial healing, reduces neointimal accumulation of smooth muscle cells and atherosclerosis in several animal models. The aim of this review is to highlight how various experimental models enabled the progress in the cellular and molecular mechanisms underlying the accelerative E2 effect on arterial endothelial healing through the estrogen receptor (ER) α, the main receptor mediating the physiological effects of estrogens. We first summarize the different experimental procedures used to reproduce vascular injury. We then provide an overview of how the combination of transgenic mouse models impacting ERα signalling with pharmacological tools demonstrated the pivotal role of non-genomic actions of ERα in E2-induced endothelial repair. Finally, we describe recent advances in the action of selective estrogen receptor modulators (SERMs) on this beneficial vascular effect, which surprisingly involves different cell types and activates different ERα subfunctions compared to E2.

Published
2021

2. Membrane estrogen receptor alpha (ERα) participates in flow-mediated dilation in a ligand-independent manner

Author

Laurent Loufrani, Marine Adlanmerini, Jean-Marie Foidart, Chanaelle Fébrissy, Julie Favre, Jean-Françoise Arnal, Vincent Procaccio, Rana Zahreddine, Léa Réthoré, Coralyne Proux, Emilie Vessieres, Linda Grimaud, Jordan Rivron, Manuela Cl Garcia, Coralie Fontaine, Gilles Flouriot, Anne-Laure Guihot, Daniel Henrion, Morgane Davezac, Françoise Lenfant, MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Maladies Métaboliques et Casdiovasculaires (UPS/Inserm U1297 - I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-Research), Université de Liège, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), FRM - DPC20171138957, Fondation pour la Recherche Médicale, Equipe FRM DEQ20160334924, Fondation pour la Recherche Médicale, ANR-18-CE14-0016-01, Agence Nationale de la Recherche, Fondation Lefoulon Delalande, Institut National de la Santé et de la Recherche Médicale, Université de Toulouse, Région Occitanie Pyrénées-Méditerranée, Institut Universitaire de France, ANR-18-CE14-0016,EstroShear,Rôle du récepteur aux œstrogènes alpha dans la mécanotransduction du flux: conséquences physiopathologiques(2018), Henrion, Daniel, APPEL À PROJETS GÉNÉRIQUE 2018 - Rôle du récepteur aux œstrogènes alpha dans la mécanotransduction du flux: conséquences physiopathologiques - - EstroShear2018 - ANR-18-CE14-0016 - AAPG2018 - VALID, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, Membrane estrogen receptor, medicine.medical_treatment, [SDV]Life Sciences [q-bio], 030204 cardiovascular system & hematology, Ligands, medicine.disease_cause, Mice, 0302 clinical medicine, cell biology, blood flow, Biology (General), 0303 health sciences, Chemistry, General Neuroscience, resistance arteries, estrogen receptors, General Medicine, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Blood Circulation, Medicine, Female, Acetylcholine, Research Article, medicine.drug, Agonist, medicine.medical_specialty, endothelium, medicine.drug_class, QH301-705.5, Science, Alpha (ethology), General Biochemistry, Genetics and Molecular Biology, shear stress, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, medicine, Animals, mouse, 030304 developmental biology, General Immunology and Microbiology, Insulin, Estrogen Receptor alpha, Hydrogen Peroxide, Endocrinology, Estrogen receptor alpha, Ex vivo, Oxidative stress
Abstract

Estrogen receptor alpha (ERα) activation by estrogens prevents atheroma through its nuclear action, whereas plasma membrane-located ERα accelerates endothelial healing. The genetic deficiency of ERα was associated with a reduction in flow-mediated dilation (FMD) in one man. Here, we evaluated ex vivo the role of ERα on FMD of resistance arteries. FMD, but not agonist (acetylcholine, insulin)-mediated dilation, was reduced in male and female mice lacking ERα (Esr1-/- mice) compared to wild-type mice and was not dependent on the presence of estrogens. In C451A-ERα mice lacking membrane ERα, not in mice lacking AF2-dependent nuclear ERα actions, FMD was reduced, and restored by antioxidant treatments. Compared to wild-type mice, isolated perfused kidneys of C451A-ERα mice revealed a decreased flow-mediated nitrate production and an increased H2O2 production. Thus, endothelial membrane ERα promotes NO bioavailability through inhibition of oxidative stress and thereby participates in FMD in a ligand-independent manner.

Published
2021

3. Estetrol prevents western diet-induced obesity and atheroma independently of hepatic estrogen receptor (ER)α

Author

Françoise Lenfant, Rana Zahreddine, Jean-François Arnal, Melissa Buscato, Pierre Gourdy, Cedric Moro, Jean-Michel Foidart, Coralie Fontaine, Marine Adlanmerini, Morgane Davezac, Raphaël Métivier, Marianne Fillet, Gaël Cobraiville, Chard-Hutchinson, Xavier, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Liège, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Agence Nationale de la Recherche, Fondation de France, Fondation pour la Recherche Médicale, Mithra Pharmaceuticals, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Hôpital de Rangueil, and CHU Toulouse [Toulouse]

Subjects
0301 basic medicine, Physiology, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Estrogen receptor, menopause, Mice, chemistry.chemical_compound, 0302 clinical medicine, Mice, Knockout, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Estetrol, Fatty liver, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Lipids, Plaque, Atherosclerotic, 3. Good health, Menopause, [SDV] Life Sciences [q-bio], Adipose Tissue, Liver, Female, estrogen receptor, medicine.medical_specialty, medicine.drug_class, Ovariectomy, 030209 endocrinology & metabolism, metabolic syndrome, 03 medical and health sciences, Physiology (medical), Internal medicine, medicine, Animals, Obesity, fatty liver, business.industry, Cholesterol, Estrogen Receptor alpha, Glucose Tolerance Test, medicine.disease, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, Receptors, LDL, chemistry, Diet, Western, Estrogen, Hepatocytes, Steatosis, Metabolic syndrome, atherosclerosis, business
Abstract

Estetrol (E4), a natural estrogen synthesized by the human fetal liver, is currently evaluated in phase III clinical studies as a new menopause hormone therapy. Indeed, E4 significantly improves vasomotor and genito-urinary menopausal symptoms and prevents bone demineralization. Compared with other estrogens, E4 was found to have limited effects on coagulation factors in the liver of women allowing to expect less thrombotic events. To fully delineate its clinical potential, the aim of this study was to assess the effect of E4 on metabolic disorders. Here, we studied the pathophysiological consequences of a Western diet (42% kcal fat, 0.2% cholesterol) in ovariectomized female mice under chronic E4 treatment. We showed that E4 reduces body weight gain and improves glucose tolerance in both C57Bl/6 and LDLR-/- mice. To evaluate the role of hepatic estrogen receptor (ER) α in the preventive effect of E4 against obesity and associated disorders such as atherosclerosis and steatosis, mice harboring a hepatocyte-specific ERα deletion (LERKO) were crossed with LDLR-/- mice. Our results demonstrated that, whereas liver ERα is dispensable for the E4 beneficial actions on obesity and atheroma, it is necessary to prevent steatosis in mice. Overall, these findings suggest that E4 could prevent metabolic, hepatic, and vascular disorders occurring at menopause, extending the potential medical interest of this natural estrogen as a new hormonal treatment.NEW & NOTEWORTHY Estetrol prevents obesity, steatosis, and atherosclerosis in mice fed a Western diet. Hepatic ERα is necessary for the prevention of steatosis, but not of obesity and atherosclerosis.

Published
2021

4. Tamoxifen Accelerates Endothelial Healing by Targeting ERα in Smooth Muscle Cells

Author

Alexia Vinel, Marie-Ange Renault, Françoise Lenfant, Emeline Lhuillier, Adrien Lupieri, Alain-Pierre Gadeau, Natalia F. Smirnova, Melissa Buscato, Morgane Davezac, Coralie Fontaine, Romain Solinhac, Raphaël Métivier, Gilles Flouriot, Emilie Vessieres, Rana Zahreddine, Jean-François Arnal, Daniel Henrion, Muriel Laffargue, Chard-Hutchinson, Xavier, APPEL À PROJETS GÉNÉRIQUE 2018 - Rôle du récepteur aux œstrogènes alpha dans la mécanotransduction du flux: conséquences physiopathologiques - - EstroShear2018 - ANR-18-CE14-0016 - AAPG2018 - VALID, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases, Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), The work at INSERM U1048 was supported by INSERM, CHU and Université de Toulouse III, Faculté de Médecine de Toulouse, ANR (EstroShear, ANR-18-CE14-0016-01), Fondation de France, Institut Universitaire de France and Region Occitanie (REGENEV). Work at the CNRS UMR6290 was supported by the CNRS and University of Rennes1., ANR-18-CE14-0016,EstroShear,Rôle du récepteur aux œstrogènes alpha dans la mécanotransduction du flux: conséquences physiopathologiques(2018), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université Fédérale Toulouse Midi-Pyrénées, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut de médecine moléculaire de Rangueil (I2MR), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Time Factors, Physiology, [SDV]Life Sciences [q-bio], Estrogen receptor, receptors, endovascular repair, 030204 cardiovascular system & hematology, Muscle, Smooth, Vascular, smooth muscle, 0302 clinical medicine, vascular, estrogen, Medicine, Receptor, skin and connective tissue diseases, Estradiol, tamoxifen, 3. Good health, [SDV] Life Sciences [q-bio], Carotid Arteries, medicine.anatomical_structure, Female, Cardiology and Cardiovascular Medicine, vascular endothelium, hormones, hormone substitutes, and hormone antagonists, Signal Transduction, medicine.drug, Selective Estrogen Receptor Modulators, Endothelium, endothelium, medicine.drug_class, Myocytes, Smooth Muscle, estrogen receptor (ERα), Mice, Transgenic, Article, 03 medical and health sciences, Breast cancer, Animals, smooth muscle cell, Wound Healing, business.industry, Estrogen Receptor alpha, Antagonist, Endothelial Cells, medicine.disease, Mice, Inbred C57BL, Demineralization, Disease Models, Animal, 030104 developmental biology, Estrogen, Tamoxifen and E2 Effects On Reendothelialization Endothelium/Vascular Type/Nitric Oxide Treatment Vascular Biology Estrogen, Cancer research, Carotid Artery Injuries, business, Tamoxifen
Abstract

Rationale: Tamoxifen prevents the recurrence of breast cancer and is also beneficial against bone demineralization and arterial diseases. It acts as an ER (estrogen receptor) α antagonist in ER-positive breast cancers, whereas it mimics the protective action of 17β-estradiol in other tissues such as arteries. However, the mechanisms of these tissue-specific actions remain unclear. Objective: Here, we tested whether tamoxifen is able to accelerate endothelial healing and analyzed the underlying mechanisms. Methods and Results: Using 3 complementary mouse models of carotid artery injury, we demonstrated that both tamoxifen and estradiol accelerated endothelial healing, but only tamoxifen required the presence of the underlying medial smooth muscle cells. Chronic treatment with 17β-estradiol and tamoxifen elicited differential gene expression profiles in the carotid artery. The use of transgenic mouse models targeting either whole ERα in a cell-specific manner or ERα subfunctions (membrane/extranuclear versus genomic/transcriptional) demonstrated that 17β-estradiol-induced acceleration of endothelial healing is mediated by membrane ERα in endothelial cells, while the effect of tamoxifen is mediated by the nuclear actions of ERα in smooth muscle cells. Conclusions: Whereas tamoxifen acts as an antiestrogen and ERα antagonist in breast cancer but also on the membrane ERα of endothelial cells, it accelerates endothelial healing through activation of nuclear ERα in smooth muscle cells, inviting to revisit the mechanisms of action of selective modulation of ERα.

Published
2020

5. Mutation of Arginine 264 on ERα (Estrogen Receptor Alpha) Selectively Abrogates the Rapid Signaling of Estradiol in the Endothelium Without Altering Fertility

Author

Muriel Le Romancer, Isabelle Raymond-Letron, Anne-Laure Guihot, Chanaelle Fébrissy, Frédéric Boudou, Raphaël Métivier, Melissa Buscato, Coralie Fontaine, Romain Solinhac, Julie Favre, Emilie Vessières, Rana Zahreddine, Claes Ohlsson, Françoise Lenfant, Pierre Gourdy, Marine Adlanmerini, Jean-François Arnal, Pierre Chambon, Typhaine Anquetil, Daniel Henrion, Henrik Laurell, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Sahlgrenska Academy at University of Gothenburg [Göteborg], Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), This work was also supported by the INSERM, the Université de Toulouse III, the Fondation pour la Recherche Médicale), The Région Midi-Pyrénées and FEDER (Fonds européen de développement régional (REGEN-EVE), the ANR (Agence Nationale de la Recherche, Estroshear, contract # ANR-18-CE14-0016-01), the CNRS, the University of Rennes1. M.A. was supported by grant from the Ministere de la Recherche. C.F was supported by ANR-18-CE14-0016-0, ANR-18-CE14-0016,EstroShear,Rôle du récepteur aux œstrogènes alpha dans la mécanotransduction du flux: conséquences physiopathologiques(2018), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université de Toulouse (UT), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Jonchère, Laurent, APPEL À PROJETS GÉNÉRIQUE 2018 - Rôle du récepteur aux œstrogènes alpha dans la mécanotransduction du flux: conséquences physiopathologiques - - EstroShear2018 - ANR-18-CE14-0016 - AAPG2018 - VALID, and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, Time Factors, Arginine, medicine.medical_treatment, [SDV]Life Sciences [q-bio], arginine, medicine.disease_cause, 0302 clinical medicine, Re-Epithelialization, Alanine, fertility, 0303 health sciences, Mutation, Chemistry, Estrogen Replacement Therapy, Mesenteric Arteries, [SDV] Life Sciences [q-bio], Vasodilation, medicine.anatomical_structure, Female, Cardiology and Cardiovascular Medicine, Signal Transduction, medicine.medical_specialty, mice, Endothelium, Nitric Oxide Synthase Type III, endothelium, Ovariectomy, Estrous Cycle, Vascular Remodeling, Steroid, 03 medical and health sciences, In vivo, estrogen receptor alpha, Internal medicine, estradiol, medicine, Animals, Point Mutation, 030304 developmental biology, Cell Proliferation, Uterus, Estrogens, Atherosclerosis, Enzyme Activation, Mice, Inbred C57BL, Endocrinology, vascular diseases, Endothelium, Vascular, Carotid Artery Injuries, Estrogen receptor alpha, 030217 neurology & neurosurgery, Cysteine
Abstract

Objective: ERα (estrogen receptor alpha) exerts nuclear genomic actions and also rapid membrane-initiated steroid signaling. The mutation of the cysteine 451 into alanine in vivo has recently revealed the key role of this ERα palmitoylation site on some vasculoprotective actions of 17β-estradiol (E2) and fertility. Here, we studied the in vivo role of the arginine 260 of ERα which has also been described to be involved in its E2-induced rapid signaling with PI-3K (phosphoinositide 3-kinase) as well as G protein in cultured cell lines. Approach and Results: We generated a mouse model harboring a point mutation of the murine counterpart of this arginine into alanine (R264A-ERα). In contrast to the C451A-ERα , the R264A-ERα females are fertile with standard hormonal serum levels and normal control of hypothalamus-pituitary ovarian axis. Although R264A-ERα protein abundance was normal, the well-described membrane ERα–dependent actions of estradiol, such as the rapid dilation of mesenteric arteries and the acceleration of endothelial repair of carotid, were abrogated in R264A-ERα mice. In striking contrast, E2-regulated gene expression was highly preserved in the uterus and the aorta, revealing intact nuclear/genomic actions in response to E2. Consistently, 2 recognized nuclear ERα-dependent actions of E2, namely atheroma prevention and flow-mediated arterial remodeling were totally preserved. Conclusions: These data underline the exquisite role of arginine 264 of ERα for endothelial membrane-initiated steroid signaling effects of E2 but not for nuclear/genomic actions. This provides the first model of fertile mouse with no overt endocrine abnormalities with specific loss-of-function of rapid ERα signaling in vascular functions.

Published
2020

6. Predominant Role of Nuclear Versus Membrane Estrogen Receptor α in Arterial Protection: Implications for Estrogen Receptor α Modulation in Cardiovascular Prevention/Safety

Author

Rana Zahreddine, Laurent Loufrani, Emmanuel Guivarc’H, Françoise Lenfant, Daniel Henrion, Jean-Michel Foidart, Anne-Laure Guihot, Emilie Vessières, Linda Grimaud, Coralie Fontaine, Nada Joe Melhem, Julie Favre, Melissa Buscato, Jean-François Arnal, Benita S. Katzenellenbogen, Pierre Gourdy, John A. Katzenellenbogen, Claude Knauf, Jamal Wakim, Marine Adlanmerini, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Illinois at Urbana-Champaign [Urbana], and University of Illinois System

Subjects
0301 basic medicine, Membrane estrogen receptor, medicine.medical_treatment, Estrogen receptor, Blood Pressure, 030204 cardiovascular system & hematology, chemistry.chemical_compound, 0302 clinical medicine, Vascular Disease, estrogen, Medicine, Coronary Heart Disease, nuclear receptor, Original Research, Mice, Knockout, Estradiol, Estetrol, Hormone replacement therapy (menopause), Arteries, Plaque, Atherosclerotic, Remodeling, Female, Cardiology and Cardiovascular Medicine, Signal Transduction, Agonist, medicine.medical_specialty, hypertension, medicine.drug_class, Aortic Diseases, Vascular Remodeling, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Animals, Transcription factor, Cell Nucleus, business.industry, Cell Membrane, Estrogen Receptor alpha, Estrogens, Atherosclerosis, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Endocrinology, Nuclear receptor, chemistry, Receptors, LDL, Estrogen, business, arteriolar remodeling
Abstract

Background Although estrogen receptor α ( ER α) acts primarily as a transcription factor, it can also elicit membrane‐initiated steroid signaling. Pharmacological tools and transgenic mouse models previously highlighted the key role of ER α membrane‐initiated steroid signaling in 2 actions of estrogens in the endothelium: increase in NO production and acceleration of reendothelialization. Methods and Results Using mice with ER α mutated at cysteine 451 (ERaC451A), recognized as the key palmitoylation site required for ER α plasma membrane location, and mice with disruption of nuclear actions because of inactivation of activation function 2 (ERaAF20 = ERaAF2°), we sought to fully characterize the respective roles of nuclear versus membrane‐initiated steroid signaling in the arterial protection conferred by ER α. ERaC451A mice were fully responsive to estrogens to prevent atheroma and angiotensin II –induced hypertension as well as to allow flow‐mediated arteriolar remodeling. By contrast, ER α AF 20 mice were unresponsive to estrogens for these beneficial vascular effects. Accordingly, selective activation of nuclear ER α with estetrol was able to prevent hypertension and to restore flow‐mediated arteriolar remodeling. Conclusions Altogether, these results reveal an unexpected prominent role of nuclear ER α in the vasculoprotective action of estrogens with major implications in medicine, particularly for selective nuclear ER α agonist, such as estetrol, which is currently under development as a new oral contraceptive and for hormone replacement therapy in menopausal women.

Published
2018

7. The Impact of Estrogen Receptor in Arterial and Lymphatic Vascular Diseases

Author

Coralie Fontaine, Florent Morfoisse, Florence Tatin, Audrey Zamora, Rana Zahreddine, Daniel Henrion, Jean-François Arnal, Françoise Lenfant, and Barbara Garmy-Susini

Subjects
Estrogen Receptor alpha, Estrogens, Review, Arteries, arterial, endothelial cells, lcsh:Chemistry, lymphatic, Sex Factors, lcsh:Biology (General), lcsh:QD1-999, Receptors, Estrogen, Animals, Humans, Disease Susceptibility, Endothelium, Vascular Diseases, lcsh:QH301-705.5, hormones, hormone substitutes, and hormone antagonists, Biomarkers, ERα, Lymphatic Vessels
Abstract

The lower incidence of cardiovascular diseases in pre-menopausal women compared to men is well-known documented. This protection has been largely attributed to the protective effect of estrogens, which exert many beneficial effects against arterial diseases, including vasodilatation, acceleration of healing in response to arterial injury, arterial collateral growth and atheroprotection. More recently, with the visualization of the lymphatic vessels, the impact of estrogens on lymphedema and lymphatic diseases started to be elucidated. These estrogenic effects are mediated not only by the classic nuclear/genomic actions via the specific estrogen receptor (ER) α and β, but also by rapid extra-nuclear membrane-initiated steroid signaling (MISS). The ERs are expressed by endothelial, lymphatic and smooth muscle cells in the different vessels. In this review, we will summarize the complex vascular effects of estrogens and selective estrogen receptor modulators (SERMs) that have been described using different transgenic mouse models with selective loss of ERα function and numerous animal models of vascular and lymphatic diseases.

Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results