Endothelial signaling at the core of neurovascular coupling: The emerging role of endothelial inward-rectifier K+ (Kir2.1) channels and N-methyl-D-aspartate receptors in the regulation of cerebral blood flow

Neurovascular coupling (NVC) represents the mechanisms whereby an increase in neuronal activity (NA) may lead to local vasodilation and increase in regional cerebral blood flow (CBF). It has long been thought that neurons and astrocytes generate the vasoactive mediators regulating local changes in CBF, whereas cerebrovascular endothelial cells are not able to directly sense NA. Unexpectedly, recent evidence demonstrated that brain microvascular endothelial cells may sense NA through inward-rectifier K+ (Kir2.1) channels and may detect synaptic activity via N-methyl-D-aspartate (NMDA) receptors (NMDARs). In the present perspective, therefore, we discuss the hypothesis that endothelial Kir2.1 channels and NMDARs play a key role in NVC and in CBF regulation, which is crucial to unravel the cellular and molecular underpinnings of blood oxygen level-dependent signals.