Platelet-Derived Growth Factor Receptor Type α Activation Drives Pulmonary Vascular Remodeling Via Progenitor Cell Proliferation and Induces Pulmonary Hypertension.

Autor: Solinc J; Sorbonne Université, INSERM, UMR_S 1166, Faculté de Médecine Pitié-Salpêtrière Paris France.; ICAN Institute Paris France., Raimbault-Machado J; Sorbonne Université, INSERM, UMR_S 1166, Faculté de Médecine Pitié-Salpêtrière Paris France.; ICAN Institute Paris France., Dierick F; Sorbonne Université, INSERM, UMR_S 1166, Faculté de Médecine Pitié-Salpêtrière Paris France.; Lady Davis Institute for Medical Research, McGill University Montréal QC Canada., El Bernoussi L; Sorbonne Université, INSERM, UMR_S 1166, Faculté de Médecine Pitié-Salpêtrière Paris France.; ICAN Institute Paris France., Tu L; Université Paris-Saclay, School of Medicine Le Kremlin-Bicêtre France.; INSERM, Hôpital Marie Lannelongue, UMR_S 999 «Pulmonary Hypertension: Pathophysiology and Novel Therapies Le Plessis-Robinson France., Thuillet R; Université Paris-Saclay, School of Medicine Le Kremlin-Bicêtre France.; INSERM, Hôpital Marie Lannelongue, UMR_S 999 «Pulmonary Hypertension: Pathophysiology and Novel Therapies Le Plessis-Robinson France., Mougenot N; Sorbonne Universités, INSERM, UMS2, Faculté de Médecine Pitié-Salpêtrière Paris France., Hoareau-Coudert B; Sorbonne Université, INSERM, Plateforme CyPS, Faculté de Médecine Pitié-Salpêtrière Paris France., Monceau V; IRSN, LRTOX Fontenay aux Roses France., Pavoine C; Sorbonne Université, INSERM, UMR_S 1166, Faculté de Médecine Pitié-Salpêtrière Paris France.; ICAN Institute Paris France., Atassi F; Sorbonne Université, INSERM, UMR_S 1166, Faculté de Médecine Pitié-Salpêtrière Paris France.; ICAN Institute Paris France., Sassoon D; Université de Paris, INSERM, Paris Cardiovascular Research Center Paris France., Marazzi G; Université de Paris, INSERM, Paris Cardiovascular Research Center Paris France., Harvey RP; Victor Chang Cardiac Research Institute Darlinghurst Australia.; St. Vincent's Clinical School and School of Biotechnology and Biomolecular Science UNSW Sydney Sydney Australia., Schofield P; St. Vincent's Clinical School and School of Biotechnology and Biomolecular Science UNSW Sydney Sydney Australia.; Immunology Division Garvan Institute of Medical Research Darlinghurst Australia., Christ D; St. Vincent's Clinical School and School of Biotechnology and Biomolecular Science UNSW Sydney Sydney Australia.; Immunology Division Garvan Institute of Medical Research Darlinghurst Australia., Humbert M; Université Paris-Saclay, School of Medicine Le Kremlin-Bicêtre France.; INSERM, Hôpital Marie Lannelongue, UMR_S 999 «Pulmonary Hypertension: Pathophysiology and Novel Therapies Le Plessis-Robinson France.; Department of Respiratory and Intensive Care Medicine Assistance Publique-Hôpitaux de Paris (AP-HP)Pulmonary Hypertension National Referral CenterHôpital Bicêtre Le Kremlin-Bicêtre France., Guignabert C; Université Paris-Saclay, School of Medicine Le Kremlin-Bicêtre France.; INSERM, Hôpital Marie Lannelongue, UMR_S 999 «Pulmonary Hypertension: Pathophysiology and Novel Therapies Le Plessis-Robinson France., Soubrier F; Sorbonne Université, INSERM, UMR_S 1166, Faculté de Médecine Pitié-Salpêtrière Paris France.; ICAN Institute Paris France., Nadaud S; Sorbonne Université, INSERM, UMR_S 1166, Faculté de Médecine Pitié-Salpêtrière Paris France.; ICAN Institute Paris France.
Jazyk: angličtina
Zdroj: Journal of the American Heart Association [J Am Heart Assoc] 2022 Apr 05; Vol. 11 (7), pp. e023021. Date of Electronic Publication: 2022 Mar 29.
DOI: 10.1161/JAHA.121.023021
Abstrakt: Background Platelet-derived growth factor is a major regulator of the vascular remodeling associated with pulmonary arterial hypertension. We previously showed that protein widely 1 (PW1 + ) vascular progenitor cells participate in early vessel neomuscularization during experimental pulmonary hypertension (PH) and we addressed the role of the platelet-derived growth factor receptor type α (PDGFRα) pathway in progenitor cell-dependent vascular remodeling and in PH development. Methods and Results Remodeled pulmonary arteries from patients with idiopathic pulmonary arterial hypertension showed an increased number of perivascular and vascular PW1 + cells expressing PDGFRα. PW1 nLacZ reporter mice were used to follow the fate of pulmonary PW1 + progenitor cells in a model of chronic hypoxia-induced PH development. Under chronic hypoxia, PDGFRα inhibition prevented the increase in PW1 + progenitor cell proliferation and differentiation into vascular smooth muscle cells and reduced pulmonary vessel neomuscularization, but did not prevent an increased right ventricular systolic pressure or the development of right ventricular hypertrophy. Conversely, constitutive PDGFRα activation led to neomuscularization via PW1 + progenitor cell differentiation into new smooth muscle cells and to PH development in male mice without fibrosis. In vitro, PW1 + progenitor cell proliferation, but not differentiation, was dependent on PDGFRα activity. Conclusions These results demonstrate a major role of PDGFRα signaling in progenitor cell-dependent lung vessel neomuscularization and vascular remodeling contributing to PH development, including in idiopathic pulmonary arterial hypertension patients. Our findings suggest that PDGFRα blockers may offer a therapeutic add-on strategy to combine with current pulmonary arterial hypertension treatments to reduce vascular remodeling. Furthermore, our study highlights constitutive PDGFRα activation as a novel experimental PH model.
Databáze: MEDLINE
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