A novel role for P450 eicosanoids in the neurogenic control of cerebral blood flow in the rat

Abstract

The P450 eicosanoids epoxyeicosatrienoic acids (EETs) are endogenous lipid mediators produced in the brain by P450 epoxygenases and metabolized through multiple pathways, including soluble epoxide hydrolase (sEH). Epoxyeicosatrienoic acids play important functions in the brain, including regulation of cerebral blood flow and protection from ischaemic brain injury. We previously demonstrated that ischaemic preconditioning induces cytochrome P450 2C11 epoxygenase (CYP2C11) expression in the brain, and that pharmacological inhibition and genetic deletion of sEH increases EETs and protects against stroke‐induced brain damage. However, the expression profiles of CYP2C11 and sEH in normal brain remain unknown. In agreement with previous reports in peripheral vessels, we here demonstrate by immunofluorescence double‐labelling that within cerebral parenchymal microvessels, sEH‐immunoreactivity (IR) is localized to the vascular smooth muscle layer. Unexpectedly, however, analysis of large cerebral conduit arteries such as the middle cerebral artery revealed CYP2C11 and sEH expression in extrinsic perivascular nerves. Double‐labelling studies revealed that CYP2C11‐ and sEH‐IR predominantly colocalized with neuronal nitric oxide synthase‐IR within perivascular nerve fibres. Significant colocalization for CYP2C11 and sEH was also observed with the parasympathetic markers vasoactive intestinal peptide and choline actetyltransferase, in addition to the sensory fibre markers calcitonin gene‐related peptide and substance P. No colocalization was observed for either CYP2C11 or sEH with the sympathetic nerve markers dopamine β‐hydroxylase or neuropeptide Y. The presence of enzymes involved in production and inactivation of EETs within extrinsic parasympathetic and sensory vasodilator fibres suggests a novel role for EETs in the neurogenic control of cerebral arteries.