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.

Taking advantage of PASMCs from idiopathic pulmonary arterial hypertension (IPAH)-patients and two mouse strains characterized by SMC-specific Piezo1-knockout, 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).

Piezo1 expression and proliferation was enhanced in PASMCs from IPAH-patients and mice PASMCs upon hypoxic exposure. SMC-specific Piezo1-deletion prevented the hypoxia-induced increase in proliferation. Moreover, Piezo1-knockout reduced hypoxic pulmonary vasoconstriction (HPV) in isolated, perfused and ventilated mouse lungs, pulmonary arteries and hemodynamic measurements in vivo. Consequently, Piezo1-deficient mice were significantly protected against CHPH-development with ameliorated right heart hypertrophy and improved hemodynamic function.

This study provides evidence for Piezo1 expressed in PASMCs being critically involved in the pathogenesis of PH – most likely by controlling pulmonary vascular tone and arterial remodeling.