Functional Role of Piezo1 in Regulating Whole-Lung Vascular Reactivity

21 July 2026

Sophia Parmisano, Jiyuan Chen, Yuqin Chen, Pritesh P. Jain, Lauren Yung, Wei-Ting Wang, Ting Wang, Xiang Li, Angela Balistrieri, Sophia A. Ferrizzi, Cassia Pedron, Owen Brooks, Mona Alotaibi, Jian Wang, Joe G.N. Garcia, Patricia A. Thistlethwaite, Ayako Makino, Jason X.-J. Yuan

https://doi.org/10.1002/pul2.70371 

 

Abstract

Mechanosensitive cation channels expressed in pulmonary arterial smooth muscle (SMC) and endothelial (EC) cells contribute to the regulation of vasoconstriction and vasodilation of the pulmonary vasculature. Here, we report that activating Piezo1, a mechanosensitive cation channel, with Yoda1 induced a mild increase in pulmonary arterial pressure (PAP) via vasoconstriction in the intact pulmonary vascular system. Inhibition of nitric oxide (NO) synthase (NOS) with L-NAME significantly potentiated Yoda1-mediated pulmonary vasoconstriction. The Yoda1-mediated vasoconstriction was inhibited by Gd3+, a non-selective blocker of cation channels, but not affected by nifedipine, a dihydropyridine blocker of voltage-dependent Ca2+ channels (VDCC). Alveolar hypoxia alone increased PAP via hypoxic pulmonary vasoconstriction (HPV); Yoda1-mediated pulmonary vasoconstriction overlaps with HPV in the isolated and perfused/ventilated lung. On top of the Yoda1-mediated increase in PAP, intrapulmonary perfusion of high K+ (25 mM) solution or phenylephrine (PE, 30 µM) induced an additional increase in PAP. These data indicate that, under normal conditions, the activation of Piezo1 (by Yoda1) caused pulmonary vasodilation due to Ca2+-associated activation of NOS in ECs and vasoconstriction due to Ca2+ influx in SMCs. In conclusion, Piezo1 or Ca2+ influx through Piezo1 in ECs and SMCs functions differently in the regulation of pulmonary vasculature. When the endothelium-derived relaxing factor (e.g., NO) is decreased due to EC injury and/or inflammation, Piezo1 or Ca2+ influx through Piezo1 channels is an important trigger for pulmonary vasoconstriction in the whole-lung vascular system.

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