ORAI Ca2+ Channels and STIM1 Drive Capillary-to-Arteriole Communication in Neurovascular Coupling

Abstract

Neurovascular coupling (NVC), initiated by the brain’s dense capillary network, matches blood flow to neuronal activity, yet key underlying mechanisms remain unresolved. We found that ORAI1 channels and their regulator STIM1, the main drivers of store-operated Ca2+ entry, are essential for communicating neuronal metabolic need, detected by capillaries, to upstream arterioles, which dilate to increase regional flow. Endothelial cell-specific knockout of either Stim1 or Orai1 disrupted capillary Ca2+ signals, impaired capillary-driven arteriole dilation, and reduced whisker stimulation-evoked increases in blood flow in the somatosensory cortex. Mice with endothelial cell-specific deficiency of Stim1, Orai1, or Orai3 showed isoform-specific behavioral aberrations, linking impaired capillary-to-arteriole signaling to cognitive decline and anxiety. These findings demonstrate that intravascular communication mediated by ORAI channels and STIM1 is fundamental for NVC and brain health.