ORAI Ca²⁺ channels and STIM1 drive capillary-to-arteriole communication in neurovascular coupling

Neurovascular coupling (NVC), which is initiated by the brain's dense capillary network, matches blood flow to neuronal activity. We found that ORAI1 channels and their regulator STIM1, the main drivers of store-operated Ca²⁺ entry, were essential for communication from capillaries, which detect neuronal metabolic need, to upstream arterioles, which dilate to increase regional flow. Endothelial cell-specific knockout of either Stim1 or Orai1 disrupted capillary Ca²⁺ signals, impaired sustained capillary-driven arteriole dilation, and reduced increases in blood flow in the somatosensory cortex evoked by whisker stimulation, indicating that ORAI1 and STIM1 sustain cerebral blood flow during prolonged neuronal stimulation. Moreover, mice with endothelial cell-specific deficiency of Stim1 or Orai1 showed cognitive impairment, whereas mice with endothelial cell-specific deficiency of Orai3 showed anxiety-like behaviors. These in vivo results link impaired capillary-to-arteriole signaling to isoform-specific behavioral aberrations. These findings demonstrate that intravascular communication mediated by ORAI channels and STIM1 is fundamental for NVC and brain health.