The role of the endothelial NPYR1-TRPC3-ET1 signaling axis in neurovascular coupling dysfunction

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This R01 application focuses on the underlying mechanisms of neurovascular coupling dysfunction. The brain consumes a large amount of energy which must be supplied as oxygen and glucose by blood flow. Neurovascular coupling, a mechanism that matches local neuronal activity to blood flow, is critical to maintain local microenvironment and normal brain function. However, normal neurovascular coupling is disrupted in seizure, traumatic brain injury, and other neurological disorders. Despite continued high neuronal metabolism, small cerebral arteries and arterioles begin to inappropriately constrict to limit CBF to the challenged neurons. This pathogenic vasoconstriction, termed the “inverse hemodynamic response” (IHR), is thought to contribute to brain damage and functional impairment in these neurological diseases. The mechanism of IHR is unknown. This proposal seeks to test a novel hypothesis that seizure-induced IHR is mediated by an endothelial signaling pathway consisted of Neuropeptide Y Receptor 1 (NPYR1), Transient Receptor Potential (Canonical) 3 (TRPC3) channels, and endothelin 1 (ET1). We generated inducible and brain-specific endothelial TRPC3 knockout line and NPYR1 knockout line. These novel mouse lines will be used in combination with NPYR1, TRPC3 and ET1 receptor selective inhibitors to test our hypothesis. Aim 1 will demonstrate the existence of an endothelial NPYR1-TRPC3-ET1 signaling pathway that mediates cerebral vasoconstriction using acutely isolated brain parenchymal arterioles and cranial window preparations in vivo. Aim 2 will show that the same signaling pathway mediates seizure-induced IHR. Aim 3 will determine whether disruption of this signaling pathway will reduce susceptibility to seizures and their deleterious consequences. The studies rely on complementary areas of expertise pooled by a research team with expertise in cerebrovascular reactivity, epilepsy and neuroinflammation and neurodegeneration. Collectively, these experiments will reveal new mechanistic insights regarding IHR and may lead to new treatments for epilepsy and other neurological diseases.