Piezo1 in Pulmonary Arterial Smooth Muscle Cells – A Critical Player for the Development of Hypoxia-induced Pulmonary Hypertension

Abstract Introduction Pulmonary hypertension (PH) is a life-threatening and progressive, but yet incurable disease. The hallmarks of PH comprise sustained contraction and excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs). A major stimulus to which PASMCs are exposed during PH development is altered mechanical stress. Mechanosensitive ion channels, such as Piezo1, perceive such mechanical stimuli and translate them into various cellular responses. Thus, the objective of the present study was to elucidate the specific role of Piezo1 in PASMCs for PH-development and progression. Methods Taking advantage of PASMCs from idiopathic pulmonary arterial hypertension (IPAH)-patients and two mouse strains characterized by SMC-specific Piezo1 knock-out, we assessed the SMC-specific role of Piezo1 in PH-development and progression via experiments in isolated, perfused and ventilated mouse lungs, wire myography and proliferation assays. In vivo function of SMC-specific Piezo1 knockout was evaluated upon induction of chronic hypoxia-induced PH (CHPH) with insights into pulmonary vascular cell senescence. Results Compared to healthy controls, PASMCs from PH-patients featured an elevated Piezo1-expression and increased proliferative phenotype. SMC-specific Piezo1-deletion, as confirmed via qPCR and patch clamp recordings, prevented the hypoxia-induced increase in PASMC-proliferation in mice. Moreover, Piezo1-knockout reduced hypoxic pulmonary vasoconstriction (HPV) in isolated, perfused and ventilated mouse lungs, endothelial-denuded pulmonary arteries and hemodynamic measurements in vivo. Consequently, Piezo1-deficient mice were considerably protected against CHPH-development with ameliorated right heart hypertrophy and improved hemodynamic function. In addition, distal pulmonary capillaries were preserved in the Piezo1-knockout mice, associated with a lower number of senescent endothelial cells. Conclusions This study provides evidence that Piezo1 expressed in PASMCs is critically involved in the pathogenesis of PH – by controlling pulmonary vascular tone, and arterial remodeling, and associated lung capillary rarefaction due to endothelial cell senescence.