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

Solinc, Julien and Raimbault‐Machado, Jessica and Dierick, France and El Bernoussi, Lamiaa and Tu, Ly and Thuillet, Raphaël and Mougenot, Nathalie and Hoareau‐Coudert, Bénédicte and Monceau, Virginie and Pavoine, Catherine and Atassi, Fabrice and Sassoon, David and Marazzi, Giovanna and Harvey, Richard P. and Schofield, Peter and Christ, Daniel and Humbert, Marc and Guignabert, Christophe and Soubrier, Florent and Nadaud, Sophie (2022) Platelet‐Derived Growth Factor Receptor Type α Activation Drives Pulmonary Vascular Remodeling Via Progenitor Cell Proliferation and Induces Pulmonary Hypertension. Journal of the American Heart Association, 11 (7). ISSN 2047-9980

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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 alpha (PDGFRalpha) 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 PDGFRalpha. 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, PDGFRalpha 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 PDGFRalpha 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 PDGFRalpha activity. Conclusions These results demonstrate a major role of PDGFRalpha 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 PDGFRalpha 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 PDGFRalpha activation as a novel experimental PH model.

Item Type: Article
Subjects: R Medicine > R Medicine (General)
Depositing User: Repository Administrator
Date Deposited: 07 Jun 2022 04:27
Last Modified: 17 Jun 2022 01:41

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