Endothelial GqPCR activity controls capillary electrical signaling and brain blood flow through PIP₂ depletion

Brain capillaries play a critical role in sensing neural activity and translating it into dynamic changes in cerebral blood flow to serve the metabolic needs of the brain. The molecular cornerstone of this mechanism is the capillary endothelial cell inward rectifier K⁺ (Kir2.1) channel, which is activated by neuronal activity-dependent increases in external K⁺ concentration, producing a propagating hyperpolarizing electrical signal that dilates upstream arterioles. Here, we identify a key regulator of this process, demonstrating that phosphatidylinositol 4,5-bisphosphate (PIP₂) is an intrinsic modulator of capillary Kir2.1-mediated signaling. We further show that PIP₂ depletion through activation of G_q protein-coupled receptors (G_qPCRs) cripples capillary-to-arteriole signal transduction in vitro and in vivo, highlighting the potential regulatory linkage between G_qPCR-dependent and electrical neurovascular-coupling mechanisms. These results collectively show that PIP₂ sets the gain of capillary-initiated electrical signaling by modulating Kir2.1 channels. Endothelial PIP₂ levels would therefore shape the extent of retrograde signaling and modulate cerebral blood flow.