Local IP₃ receptor-mediated Ca²⁺ signals compound to direct blood flow in brain capillaries

Healthy brain function depends on the finely tuned spatial and temporal delivery of blood-borne nutrients to active neurons via the vast, dense capillary network. Here, using in vivo imaging in anesthetized mice, we reveal that brain capillary endothelial cells control blood flow through a hierarchy of IP₃ receptor-mediated Ca²⁺ events, ranging from small, subsecond protoevents, reflecting Ca²⁺ release through a small number of channels, to high-amplitude, sustained (up to ~1 min) compound events mediated by large clusters of channels. These frequent (~5000 events/s per microliter of cortex) Ca²⁺ signals are driven by neuronal activity, which engages G_q protein-coupled receptor signaling, and are enhanced by Ca²⁺ entry through TRPV4 channels. The resulting Ca²⁺-dependent synthesis of nitric oxide increases local blood flow selectively through affected capillary branches, providing a mechanism for high-resolution control of blood flow to small clusters of neurons.