Mechanism of neuro‐vascular unit regulation by glutamate

Proper coupling between neuronal activity and cerebral blood flow is essential for brain function. The neurons, their surrounding glia and microvessels represent the neurovascular unit (NVU). A fundamental gap exists in our understanding of the mechanism(s) by which neuro‐vascular regulation via glial astrocytes occurs and how disease impacts this vital function. Ischemic events including stroke may be associated with NVU dysregulation (increased vascular tone, decreased vasodilation). It is not completely understood if and how the main neurotransmitters (Glutamate, adenosine tri‐phophate and D‐serine) interact with the glia and/or microvessels to cause vessel dilation. Here we present a new ex vivo model of the NVU consisting of isolated penetrating arterioles placed on astrocytes and stimulated with the neurotransmitter glutamate as neuronal surrogate. Using this novel ex vivo model of the NVU, we determined that glutamate has no effect on arteriolar diameter but interacts with astrocytes to induce astrocyte‐mediated arteriolar dilation via distinct mechanisms. Importantly, dilation to Glutamate is abolished in denuded vessels while smooth muscle ‐ dependent dilation to ATP remains (see our companion poster). Further examination of the metabolic pathways involved indicates that glutamate releases a cytochrome P 450 ‐dependent mediator from the astrocyte with the large conductance calcium sensitive potassium channel (BK Ca ) as the main molecular target and, to a lesser degree, the inward rectifier Potassium channel K IR . Nitric oxide acts as a permissive factor necessary for potassium channel function. Involvement of other metabolic pathways and molecular targets on the vascular cells are discussed.These significant data indicate that astrocytes, exposed to different neurotransmitters, affect arteriolar tone via distinct molecular pathways.