CYP Enzymes in ECs

CYP enzymes are a ubiquitously expressed family of heme enzymes that play central roles in xenobiotic metabo lism and lipid oxidation. CYP-dependent arachidonate oxidation occurs through three pathways, allylic oxidation, omega hydroxylation, and olefin epoxidation. These result in a series of oxygenated metabolites, including epoxides and fatty acid alcohols.

Nonhepatic cytochrome P450 arachidonate metabolites act as intracellular signaling molecules in vascular tissue (Figure 5). The major EC CYP isoforms are prostacyclin synthase (PGI synthase) and thromboxane synthase (TXS), which generate prostacyclin (PGI2) or thromboxane A2 (TXA2), respectively, from PGHS-derived PGH2 (described earlier). Both enzymes are controlled through transcrip-tional regulation, although the pathways are not well characterized. For example, TXS is inducible in pig aortic ECs by xenoreactive antibodies, whereas IL-1b elevates PGI synthase in tandem with PGHS-2 in HUVECs.

Additional EC-derived CYP products include the epox-ides, 11,12-epoxyeicosatetraenoic acid (EET) and 5,6-EET, and dihydroxyeicosatrienoic acids (DHET). 11,12-EET is avidly esterified into endothelial phospholipid pools and mediates vascular relaxation, possibly accounting for a component of endothelial-derived hyperpolarizing factor (EDHF) activity. Preformed EETs in endothelial membranes can influence vascular function by altering membrane characteristics, ion transport, or lipid-dependent signaling pathways. For example, 5,6-EET mediates vasodilation by either increasing nitric oxide production through stimulating Ca2+ influx into ECs, including rat cerebral microvessels, or by directly activating smooth muscle Kca channels. A final important vasoactive CYP product, 20-HETE is generated by CYP 4A and promotes renal vasoconstriction. However, this is generated by smooth muscle, rather than ECs.

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