Transient receptor potential channels (TRPC) contribute to an enhanced endothelial cell proliferation and irreversible vascular remodeling associated with the development of pulmonary arterial hypertension (PAH)

Abstract

Disordered pulmonary arterial endothelial cell (PAEC) growth underlies the formation of angio‐proliferation and intimal lesions, obliterating the small pulmonary arteries (PAs), resulting in irreversible structural alterations, or pulmonary vascular remodeling in pulmonary arterial hypertension (PAH) patients.ObjectiveTo demonstrate that transient receptor potential channel (TRPC6) contributes to PAEC proliferation and in the development of PAH.ResultsPAEC isolated from Idiopathic PAH (IPAH) patients showed an enhanced VEGF‐induced [Ca2+]cyt and proliferation. In parallel, TRPC6 (mRNA and protein) expression was markedly up regulated in IPAH compared to normal subjects. Interestingly, knockdown of TRPC6 in IPAH‐PAEC using siRNA significantly attenuated VEGF‐induced rise in [Ca2+]cyt and proliferation. Deletion of either TRPC6 (TRPC6−/−) or TRPC4 (TRPC4−/−) abolished thapsigargin‐induced store Ca2+ release‐activated Ca2+ entry (SOCE) in mice PAEC. In addition, TRPC6−/− mice showed significant abrogation of hypoxia‐induced changes in the right ventricular systolic pressure and right ventricular hypertrophy suggesting its role in vascular remodeling associated with PAH.ConclusionOur studies provide a comprehensive picture of TRPC6‐mediated Ca2+ entry mechanisms in contributing to an increased PAEC proliferation and vascular remodeling associated with PAH.