Role of Piezo1 channels in regulation of pulmonary vasoconstriction and vasodilation

The pulmonary vasculature is under constant mechanical stimulation due to flow shear stress (many vascular bifurcations) and circumferential and longitudinal stretch (right ventricular stroke and respiration). Mechanic stimulation-induced vasodilation is thus important to help maintain the low pressure and resistance in the pulmonary circulation system under normal conditions. We used isolated and perfused/ventilated mouse lungs to examine pulmonary vascular reactivity in an intact lung vasculature system. Western blot experiments were performed to determine the expression and distribution of the mechanosensitive cation channel, Piezo1, in the lungs. Activation of Piezo1 with Yoda1 induced a mild increase in pulmonary arterial pressure (PAP) due to pulmonary vasoconstriction in the intact pulmonary vascular system or the isolated and perfused/ventilated lungs. Inhibition of nitric oxide (NO) synthase (NOS) with L-NAME significantly potentiated Yoda1-mediated increase in PAP. Furthermore, intrapulmonary arterial perfusion of U46619, an analog of thromboxane A 2 (TXA 2 ), also significantly enhanced the Yoda1-mediated increase in PAP. The Yoda1-mediated increase in PAP was inhibited by intrapulmonary arterial perfusion of Gd 3+ , a non-selective blocker of cation channels like Piezo1, but not significantly affected by nifedipine, a dihydropyridine voltage-dependent Ca 2+ channel blocker. Alveolar hypoxia alone resulted in an increase in PAP due to hypoxic pulmonary vasoconstriction (HPV); Yoda1-mediated pulmonary vasoconstriction overlaps with alveolar hypoxia-mediated vasoconstriction in the isolated and perfused/ventilated lungs. 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, activation of Piezo1 (by Yoda1) caused pulmonary vasodilation due to Ca 2+ -associated activation of NOS and synthesis/release of NO in endothelial cells (ECs) and pulmonary vasoconstriction due to Ca 2+ influx in smooth muscle cells (SMCs). Piezo1 or Ca 2+ 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 and/or the endothelium-derived constricting factor (e.g., TXA 2 ) is increased, due to EC injury and/or inflammation, Piezo1 or Ca 2+ influx through Piezo1 channels is an important trigger for pulmonary vasoconstriction. This study is supported in part by a grant from the NHLBI/NIH (HL171538) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.