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1. GCN2 regulates BMP signaling: consequence for PVOD pathobiology and therapeutic management

Author

Ignacio Anegon, Mélanie Lambert, Séverine Remy, Marc Humbert, Fabrice Antigny, Florent Soubrier, Olaf Mercier, Elie Fadel, Barbara Girerd, David Montani, Bahgat Soilih, Juliette Bignard, Sophie Nadaud, Grégoire Manaud, Frédéric Perros, Stjin Verleden, Monica Florio, Florence Lecerf, Banghua Sun, Gérald Simmoneau, and Olivier Claude

Subjects
In vivo, business.industry, Transgene, Extracellular, Cancer research, Medicine, Phosphorylation, Chordin, business, medicine.disease, Pulmonary hypertension, Psychological repression, BMPR2
Abstract

Introduction: Pulmonary veno-occlusive disease (PVOD) is an orphan fatal disease. The identification of biallelic inactivating mutations of EIF2AK4 (encoding GCN2) as the major genetic cause of PVOD has clarified the nosology of the disease. On the other hand, BMP/BMPR2 axis is a major axis of pulmonary arterial hypertension pathobiology, a close but better understood form of severe pulmonary hypertension (PH) Objective: To investigate the functional relationship between GCN2 and the BMP/BMPR2 axis. Methods: We investigated GCN2 and the BMP/BMPR2 axis in human and animal models of PVOD, and in cultured human pulmonary microvascular endothelial cells (hPMEC) with interventional experiments (siRNA and pharmacological inhibitors/activators) Results: Pulmonary GCN2 protein expression was decreased in all forms of PVOD. We showed that GCN2 loss-of-function negatively regulates BMP-dependent SMAD1/5/9 signaling in hPMEC. This molecular relationship was confirmed in vivo, in the lungs of a newly created transgenic rat model knock out for Eif2ak4. We found a 4 fold decrease in SMAD1/5/9 phosphorylation in KO rats. We showed this regulation may be mediated through GCN2-dependent repression of chordin, an extracellular antagonist of BMP signaling. GCN2 inhibition induced a dramatic increase in hPMEC proliferation, which is highly relevant of PVOD genesis. BMP9 treatment was able to block this exuberant proliferation Conclusion: GCN2 loss-of-function negatively regulates SMAD1/5/9 phosphorylation. Despite this dampened BMP signaling, exogenous BMP9 was still able to reverse GCN2 inhibition-induced hPMEC proliferation. BMP9 may hence be considered as potential therapeutic options for PVOD

Published
2020
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2. Comparison of Human and Experimental Pulmonary Veno-Occlusive Disease

Author

Séverine Remy, Juliette Bignard, Audrey Courboulin, Gérald Simonneau, Maria-Rosa Ghigna, Marc Humbert, Ignacio Anegon, Mélanie Lambert, Fabrice Antigny, Monica Florio, Esther J. Nossent, Banghua Sun, Harm Jan Bogaard, Elie Fadel, Aurélie Hautefort, Anton Vonk Noordegraaf, Angèle Boet, Barbara Girerd, Maria-Candida Vinhas, Grégoire Manaud, Sophie Nadaud, Frédéric Perros, Stijn E. Verleden, Olivier Claude, Sébastien J. Dumas, Florent Soubrier, Peter Dorfmüller, Benoit Ranchoux, Florence Lecerf, Olaf Mercier, David Montani, Katrien Grünberg, Centre de Référence de l’Hypertension Pulmonaire Sévère [CHU Le Kremlin Bicêtre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Hypertension pulmonaire : physiopathologie et innovation thérapeutique (HPPIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Vrije Universiteit Amsterdam [Amsterdam] (VU), Centre Chirurgical Marie Lannelongue (CCML), Génétique, pharmacologie et physiopathologie des maladies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Amgen Inc. [Thousand Oaks, CA, USA], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Service de Pneumologie et Réanimation Respiratoire (DHU TORINO), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre-Centre de Référence de l'Hypertension Pulmonaire Sévère, University of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research, Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Université Laval [Québec] (ULaval), This work was funded the French National Research Agency (Agence Nationale de la Recherche, ANR, grant: ANR-13-JSV1-0011-01) and by Pulmonary Vascular Research Institute (PVRI) BMPR2 Research Grant supported by the Dinosaur Trust (to F.P.), and by DHU TORINO (Département Hospitalo-Universitaire Thorax Innovation) and AP-HP. This work was also supported by INSERM, Université Paris-Sud, Université Paris-Saclay and Hôpital Marie Lannelongue. G.M. is 2017 Laureate of Fonds de Recherche en Santé Respiratoire et de la Fondation du Souffle. F.A. receives funding from the Fondation du Souffle et Fonds de Dotation Recherche en Santé Respiratoire, from the Fondation Lefoulon-Delalande and from the Fondation Legs Poix. F.A. also received funding from the National Funding Agency for Research: ANR-18-CE14-0023. M.L. is supported by Therapeutic Innovation Doctoral School (ED569). E.J.N. was supported by an ERS (European Respiratory Society) PAH LongTerm Research Fellowship. S.E.V is supported by a post-doctoral fellowship of FWO (12G8718N) and a grant from KU Leuven (C24/18/073)., ANR-13-JSV1-0011,EMIR,Mécanismes épigénétiques dans l'inflammation et le remodelage vasculaire de l'hypertension pulmonaire(2013), ANR-18-CE14-0023,KAPAH,KCNK3 une nouvelle cible thérapeutique dans l'hypertension artérielle pulmonaire(2018), Le Bihan, Sylvie, Jeunes Chercheuses et Jeunes Chercheurs - Mécanismes épigénétiques dans l'inflammation et le remodelage vasculaire de l'hypertension pulmonaire - - EMIR2013 - ANR-13-JSV1-0011 - JC - VALID, APPEL À PROJETS GÉNÉRIQUE 2018 - KCNK3 une nouvelle cible thérapeutique dans l'hypertension artérielle pulmonaire - - KAPAH2018 - ANR-18-CE14-0023 - AAPG2018 - VALID, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, Pathology, Centre chirurgical Marie Lannelongue, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
0301 basic medicine, Pulmonary and Respiratory Medicine, Pathology, medicine.medical_specialty, Hypertension, Pulmonary, [SDV]Life Sciences [q-bio], SMAD signaling, Clinical Biochemistry, CHOP, Pulmonary Artery, Bone morphogenetic protein, Pulmonary hypertension, 03 medical and health sciences, 0302 clinical medicine, medicine.artery, Medicine, Animals, Humans, Biology, Molecular Biology, Microvessel, Lung, business.industry, Endothelial Cells, BMPR-II, Cell Biology, medicine.disease, 3. Good health, Rats, Heme oxygenase, [SDV] Life Sciences [q-bio], Chemistry, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, 030228 respiratory system, Pulmonary artery, Mutation, Human medicine, Pulmonary Veno-Occlusive Disease, GCN2, business, Transcription Factor CHOP, pulmonary veno-occlusive disease, Signal Transduction
Abstract

Pulmonary veno-occlusive disease (PVOD) occurs in humans either as a heritable form (hPVOD) due to biallelic inactivating mutations of EIF2AK4 (encoding GCN2) or as a sporadic form in older age (sPVOD). The chemotherapeutic agent mitomycin C (MMC) is a potent inducer of PVOD in humans and in rats (MMC-PVOD). Here, we compared human hPVOD and sPVOD, and MMC-PVOD pathophysiology at the histological, cellular, and molecular levels to unravel common altered pathomechanisms. MMC exposure in rats was associated primarily with arterial and microvessel remodeling, and secondarily by venous remodeling, when PVOD became symptomatic. In all forms of PVOD tested, there was convergent GCN2-dependent but eIF2α-independent pulmonary protein overexpression of HO-1 (heme oxygenase 1) and CHOP (CCAAT-enhancer-binding protein [C/EBP] homologous protein), two downstream effectors of GCN2 signaling and endoplasmic reticulum stress. In human PVOD samples, CHOP immunohistochemical staining mainly labeled endothelial cells in remodeled veins and arteries. Strong HO-1 staining was observed only within capillary hemangiomatosis foci, where intense microvascular proliferation occurs. HO-1 and CHOP stainings were not observed in control and pulmonary arterial hypertension lung tissues, supporting the specificity for CHOP and HO-1 involvement in PVOD pathobiology. In vivo loss of GCN2 (EIF2AK4 mutations carriers and Eif2ak4-/- rats) or in vitro GCN2 inhibition in cultured pulmonary artery endothelial cells using pharmacological and siRNA approaches demonstrated that GCN2 loss of function negatively regulates BMP (bone morphogenetic protein)-dependent SMAD1/5/9 signaling. Exogenous BMP9 was still able to reverse GCN2 inhibition-induced proliferation of pulmonary artery endothelial cells. In conclusion, we identified CHOP and HO-1 inhibition, and BMP9, as potential therapeutic options for PVOD. ispartof: AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY vol:63 issue:1 pages:118-131 ispartof: location:United States status: published

Published
2020
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3. Progenitor/Stem Cells in Vascular Remodeling during Pulmonary Arterial Hypertension

Author

France Dierick, Julien Solinc, Juliette Bignard, Florent Soubrier, and Sophie Nadaud

Subjects
0301 basic medicine, QH301-705.5, vascular remodeling, Review, 030204 cardiovascular system & hematology, pericytes, 03 medical and health sciences, 0302 clinical medicine, Smooth muscle, stem cells, pulmonary arterial hypertension, Animals, Humans, Medicine, Vascular proliferation, Biology (General), Progenitor cell, Cells, Cultured, Progenitor, business.industry, Mesenchymal stem cell, progenitor cells, General Medicine, endothelial cells, smooth muscle cells, 030104 developmental biology, Cancer research, Stem cell, business, Myofibroblast
Abstract

Pulmonary arterial hypertension (PAH) is characterized by an important occlusive vascular remodeling with the production of new endothelial cells, smooth muscle cells, myofibroblasts, and fibroblasts. Identifying the cellular processes leading to vascular proliferation and dysfunction is a major goal in order to decipher the mechanisms leading to PAH development. In addition to in situ proliferation of vascular cells, studies from the past 20 years have unveiled the role of circulating and resident vascular in pulmonary vascular remodeling. This review aims at summarizing the current knowledge on the different progenitor and stem cells that have been shown to participate in pulmonary vascular lesions and on the pathways regulating their recruitment during PAH. Finally, this review also addresses the therapeutic potential of circulating endothelial progenitor cells and mesenchymal stem cells.

Published
2021
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