Caveolae in the CNS arterioles mediate neurovascular coupling

Proper brain function depends on neurovascular coupling: neural activity rapidly increases local blood flow to meet moment-to-moment changes in regional brain energy demand(1). Neurovascular coupling is the basis for functional brain imaging(2), and its impairment is implicated in neurodegeneration(1). The underlying molecular and cellular mechanisms of neurovascular coupling remain poorly understood. The conventional view is that neurons or astrocytes release vasodilatory factors that act directly on smooth muscle cells (SMC) to induce arterial dilation and increase local blood flow(1). Here, using two-photon microscopy to image neural activity and vascular dynamics simultaneously in the barrel cortex of awake mice under whisker stimulation, we found that arteriolar endothelial cells (aECs) play an active role in mediating neurovascular coupling. We found that aECs, unlike other vascular segments of ECs in the CNS, have abundant caveolae. Acute genetic perturbations that eliminated caveolae in aECs, but not in neighboring SMCs, impaired neurovascular coupling. Strikingly, caveolae function in aECs is independent of the eNOS-mediated nitric oxide (NO) pathway. Ablation of both caveolae and eNOS completely abolished neurovascular coupling, whereas each single mutant exhibited partial impairment, revealing that caveolae-mediated pathway in aECs is a major contributor to neurovascular coupling. Our findings indicate that vasodilation is largely due to ECs that actively relay signals from the CNS to SMCs via a caveolae-dependent pathway.