The factor in EDHF: Cytochrome P450 derived lipid mediators and vascular signaling

Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid to generate epoxyeicosatrienoic acids (EETs). The latter are biologically active and reported to act as an endothelium-derived hyperpolarizing factor (EDHF) as well as to affect angiogenic and inflammatory signaling pathways. In addition to arachidonic acid, the CYP epoxygenases also metabolize the Ω-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid and docosahexaenoic acid, to generate bioactive lipid epoxide mediators. The latter can be more potent than the EETs but their actions are under investigated. The Ω3-epoxides, like the EETs, are metabolized by the soluble epoxide hydrolase to corresponding diols and epoxide hydrolase inhibition increases epoxide levels and demonstrates anti-hypertensive as well as anti-inflammatory effects. It seems that the overall consequences of CYP epoxygenase activation largely depend on enzyme substrate preference and the endogenous Ω-3/Ω-6 PUFA ratio. This review outlines the evidence for a physiological role for EETs in the regulation of vascular homeostasis.