PNAS · Dec 23, 2025

PIP₂ corrects an endothelial Piezo1 channelopathy

By Hashad AM, Abd-Alhaseeb MM, Lim XR et al.

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 Gαq PCR (GqPCR) 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 GqPCR 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 GqPCR activation facilitates Piezo1 activity. Pharmacological studies revealed the involvement of Gαq and phospholipase C stimulation, as well as downstream phosphatidylinositol-4,5-bisphosphate (PIP₂) hydrolysis in Piezo1 activation, but not signaling triggered by metabolites of PIP₂ hydrolysis. Exogenous application of nanomolar-to-micromolar PIP₂ suppressed Piezo1 open probability. Brain capillary ECs from mouse models of Alzheimer's disease, cerebral small vessel disease, or Piezo1 gain-of-function mutation exhibited higher Piezo1 activity, that was corrected by exogenous ex vivo PIP₂ application. We finally tested in vivo the hypothesis that systemic PIP₂ 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.

doi.org/10.1073/pnas.2522750122Open accessPubMed 41433068Mechanisms