Figure 3.

Simplified schematic diagram of the major pathways that regulate blood flow in the cerebral NVU. Neuronal presynaptic release of glutamate (Glu) is taken up by astrocytic processes and acts on metabotropic glutamate receptors (mGluR) to raise [Ca²⁺], inducing the generation of arachidonic acid (AA) from phospholipase A2 (PLA2). The ionotropic glutamate receptors seem less important in controlling blood flow in the spinal cord, and this signaling is not shown in the figure. AA can be converted to multiple prostaglandins (PGs) (by cyclooxygenase, COX), epoxyeicosatrienoic acid (EET) (by cytochrome P450 epoxygenase, CYP450) to dilate vessels, or 20-hydroxyeicosatetraenoic acid (20-HETE) (by ω-hydroxylase, CYP4A) to constrict vessels. Raised [Ca²⁺] in astrocyte endfeet may activate Ca²⁺-gated K⁺ channels (K_Ca) to release K⁺ and activate inward rectifier K⁺ channels (KIRs) on SMCs. The metabolic process of neurons releases adenosine triphosphate (ATP) acting on metabotropic purinergic receptors (P2XR or P2YR) on astrocytes to increase intracellular Ca²⁺. The metabolic byproducts adenosine (to adenosine 2 receptor, A2R) and lactate activate ATP-sensitive potassium (K_ATP) channels, causing vessel relaxation; lactate inhibits PG transporters to cause PG accumulation or activate endothelial nitric oxide synthase (NOS) to release nitric oxide (NO), subsequently causing vasodilation. Neurons release diverse vasoactive neurotransmitters to control the NVU directly, such as vasoactive intestinal peptide (VIP) (to VIP receptor, VIPR), acetylcholine (ACh) (to muscarinic acetylcholine receptor, mAChR), dopamine (to dopamine receptor, DR), norepinephrine (to α-adrenoceptor, α-R), and NO (to cyclic guanosine monophosphate, cGMP).