Received March 9, 2007
Revised April 10, 2007
Accepted after revision April 24, 2007

¹ OHSU

^* To whom correspondence should be addressed. E-mail: alkayedn{at}ohsu.edu.

	Abstract

The P450 eicosanoids epoxyeicosatrienoic acids (EETs) are endogenous lipid mediators produced in brain by P450 epoxygenases and metabolized through multiple pathways including soluble epoxide hydrolase (sEH). EETs play important functions in brain, including cerebral blood flow regulation and protection from ischemic brain injury. We previously demonstrated that ischemic preconditioning induces cytochrome P450 2C11 epoxygenase (CYP2C11) expression in brain, and that pharmacological inhibition and genetic deletion of sEH increases bioavailable EETs and are protects against ischemic brain injury. However, the expression profiles of CYP2C11 and sEH in normal brain remain unknown. We demonstrate by immunofluorescence double-labeling that within cerebral parenchymal microvessels, sEH-immunoreactivity (IR) is localized to the vascular smooth muscle layer. Unexpectedly, analysis of large cerebral conduit arteries such as the middle cerebral artery (MCA) revealed CYP2C11 and sEH expression in extrinsic perivascular nerves. Double labeling studies revealed that CYP2C11- and sEH-IR predominantly co-localized with neuronal nitric oxide synthase (nNOS)-IR within perivascular nerve fibers. Significant co-localization for CYP2C11 and sEH was also observed with parasympathetic markers vasoactive intestinal peptide (VIP) and choline actetyltransferase (ChAT), in addition to the sensory fiber markers calcitonin gene-related peptide (CGRP) and substance P. No co-localization was observed for either CYP2C11 or sEH with the sympathetic nerve markers dopamine -hydroxylase (DBH) or neuropeptide Y (NPY). The presence of enzymes involved in EETs production and inactivation within extrinsic parasympathetic and sensory vasodilator fibers suggests a novel role for EETs in the neurogenic control of cerebral arteries.

Key Words: Brain, Neural, Vascular blood flow