Extrinsic perivascular nerves regulate regional cerebral blood flow (CBF) by innervating conduit arteries such as the middle cerebral and basilar arteries. P450 eicosanoids, or epoxyeicosatrienoic acids (EETs), are produced in astrocytes and have been identified as endogenous regulatory agents of CBF.  Interestingly, our preliminary data demonstrate that extrinsic perivascular vasodilator nerves surrounding the middle cerebral artery express cytochrome P450 2C11 epoxygenase (CYP2C11) and soluble epoxide hydrolase (sEH) – the enzymes required for synthesis and degradation of EETs, respectively.

Traditionally, parasympathetic vasodilation in cerebral vasculature has been attributed to the release of NO from perivascular nitrergic nerves. We hypothesize that EETs are parasympathetic nerve-derived relaxing factors involved in the neurogenic regulation of CBF. In this study, we will characterize the cerebral extrinsic perivascular nerve origins of EETs, CYP2C11, and sEH and define their in vivo effect on the vasodilation of cerebral conduit arteries. In addition, we will determine 1) the mechanism by which the stimulation of parasympathetic neurons (PSN) induces the release of EETs from PSN axons that extend into vascular smooth muscle cells (VSMC) and 2) the mechanism of action by EETs on VSMC to affect dilation.

We expect that our findings will enhance understanding of dysfunctional vasodilator innervation that may play a role in the pathogenesis of such cerebrovascular disorders as vasospasm following subarachnoid hemorrhage, migraine, cerebral ischemia, and Alzheimer’s disease.

Funding for this investigation is provided by an F31 grant from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health.