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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\n                    <jats:sc>L<\/jats:sc>\n                    \u2010NAME significantly potentiated Yoda1\u2010mediated pulmonary vasoconstriction. The Yoda1\u2010mediated vasoconstriction was inhibited by Gd\n                    <jats:sup>3+<\/jats:sup>\n                    , a non\u2010selective blocker of cation channels, but not affected by nifedipine, a dihydropyridine blocker of voltage\u2010dependent Ca\n                    <jats:sup>2+<\/jats:sup>\n                    channels (VDCC). Alveolar hypoxia alone increased PAP via hypoxic pulmonary vasoconstriction (HPV); Yoda1\u2010mediated pulmonary vasoconstriction overlaps with HPV in the isolated and perfused\/ventilated lung. On top of the Yoda1\u2010mediated increase in PAP, intrapulmonary perfusion of high K\n                    <jats:sup>+<\/jats:sup>\n                    (25\u2009mM) solution or phenylephrine (PE, 30\u2009\u00b5M) induced an additional increase in PAP. These data indicate that, under normal conditions, the activation of Piezo1 (by Yoda1) caused pulmonary vasodilation due to Ca\n                    <jats:sup>2+<\/jats:sup>\n                    \u2010associated activation of NOS in ECs and vasoconstriction due to Ca\n                    <jats:sup>2+<\/jats:sup>\n                    influx in SMCs. In conclusion, Piezo1 or Ca\n                    <jats:sup>2+<\/jats:sup>\n                    influx through Piezo1 in ECs and SMCs functions differently in the regulation of pulmonary vasculature. When the endothelium\u2010derived relaxing factor (e.g., NO) is decreased due to EC injury and\/or inflammation, Piezo1 or Ca\n                    <jats:sup>2+<\/jats:sup>\n                    influx through Piezo1 channels is an important trigger for pulmonary vasoconstriction in the whole\u2010lung vascular system.\n                  <\/jats:p>","DOI":"10.1002\/pul2.70371","type":"journal-article","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T08:33:19Z","timestamp":1784622799000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Functional Role of Piezo1 in Regulating Whole\u2010Lung Vascular Reactivity"],"prefix":"10.1002","volume":"16","author":[{"given":"Sophia","family":"Parmisano","sequence":"first","affiliation":[{"name":"Department of Medicine University of California, San Diego La Jolla CA 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