Astrocytes mediate neurovascular signaling to capillary pericytes but not to arterioles

Active neurons increase their energy supply by dilating nearby arterioles and capillaries. This neurovascular coupling underlies blood oxygen level-dependent functional imaging signals, but its mechanism is controversial. Canonically, neurons release glutamate to activate metabotropic glutamate receptor 5 (mGluR5) on astrocytes, evoking Ca²⁺ release from internal stores, activating phospholipase A2 and generating vasodilatory arachidonic acid derivatives. However, adult astrocytes lack mGluR5, and knockout of the inositol 1,4,5-trisphosphate receptors that release Ca²⁺ from stores does not affect neurovascular coupling. We now show that buffering astrocyte Ca²⁺ inhibits neuronally evoked capillary dilation, that astrocyte [Ca²⁺]_i is raised not by release from stores but by entry through ATP-gated channels, and that Ca²⁺ generates arachidonic acid via phospholipase D2 and diacylglycerol lipase rather than phospholipase A2. In contrast, dilation of arterioles depends on NMDA receptor activation and Ca²⁺-dependent NO generation by interneurons. These results reveal that different signaling cascades regulate cerebral blood flow at the capillary and arteriole levels.