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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,12,30]]},"abstract":"<jats:p>\n                    Brain capillaries are sensors of neural activity. When a brain region is active, capillary endothelial cells (ECs) sense neuron-derived mediators and elicit a local increase in blood flow (functional hyperemia) to support the rise in metabolic needs. This hyperemic response involves a rapid electrical component and a slower chemical component that involves G\u03b1q PCR (G\n                    <jats:sub>q<\/jats:sub>\n                    PCR) activation by agonists released from neurons. The intravascular forces associated with hyperemia engage mechanosensitive Piezo1-mediated signaling that serves a mechano-feedback control function to facilitate the return of elevated blood flow to basal levels. Whether G\n                    <jats:sub>q<\/jats:sub>\n                    PCR activity influences Piezo1 mechanosensitive signaling has not been explored, despite the potential significant implications of such crosstalk. Using patch-clamp electrophysiology and freshly isolated brain capillary ECs, we demonstrate that prostanoid or muscarinic G\n                    <jats:sub>q<\/jats:sub>\n                    PCR activation facilitates Piezo1 activity. Pharmacological studies revealed the involvement of G\u03b1q and phospholipase C stimulation, as well as downstream phosphatidylinositol-4,5-bisphosphate (PIP\n                    <jats:sub>2<\/jats:sub>\n                    ) hydrolysis in Piezo1 activation, but not signaling triggered by metabolites of PIP\n                    <jats:sub>2<\/jats:sub>\n                    hydrolysis. Exogenous application of nanomolar-to-micromolar PIP\n                    <jats:sub>2<\/jats:sub>\n                    suppressed Piezo1 open probability. Brain capillary ECs from mouse models of Alzheimer\u2019s disease, cerebral small vessel disease, or Piezo1 gain-of-function mutation exhibited higher Piezo1 activity, that was corrected by exogenous ex vivo PIP\n                    <jats:sub>2<\/jats:sub>\n                    application. We finally tested in vivo the hypothesis that systemic PIP\n                    <jats:sub>2<\/jats:sub>\n                    administration restores functional hyperemia in EC-specific Piezo1 gain-of-function mutant mice suffering impaired blood flow. Our findings provide insights into Piezo1 channel regulation and how it affects neurovascular coupling and cerebral blood flow.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2522750122","type":"journal-article","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T16:48:15Z","timestamp":1766508495000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":16,"title":["PIP\n                    <sub>2<\/sub>\n                    corrects an endothelial Piezo1 channelopathy"],"prefix":"10.1073","volume":"122","author":[{"given":"Ahmed M.","family":"Hashad","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Larner College of Medicine, Vermont Center for Cardiovascular and Brain Health, University of Vermont","place":["Burlington"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5388-5250","authenticated-orcid":false,"given":"Mohammad 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