Cytochrome P450 enzymes in vascular homeostasis

Since the initial reports that renal cytochrome P450 (CYP) enzymes can meta bolize arachidonic acid to substances which affect arterial tone, it has be come increasingly clear that CYP enzymes expressed within the cardiovascula r system play a crucial role in the modulation of vascular homeostasis. The re is strong evidence suggesting that the activation of a CYP epoxygenase i n endothelial cells is an essential step in nitric oxide and prostacyclin-i ndependent vasodilatation of several vascular beds, particularly in the hea rt and kidney. A smooth muscle CYP omega -hydroxylase, on the other hand, g enerates a vasoconstrictor eicosanoid that is central to the myogenic respo nse. Moreover, CYP epoxygenase and omega -hydroxylase products, as well as CYP-derived reactive oxygen species, are intracellular signal transduction molecules involved in several signaling cascades affecting numerous cellula r processes, including vascular cell proliferation and angiogenesis. This r eview summarizes the vascular effects of epoxyeicosatrienoic acids and 20-h ydroxyeicosatetraenoic acid, both of which are CYP-derived metabolites of a rachidonic acid, endogenously generated within endothelial and vascular smo oth muscle cells. Although the link between CYP expression/activity and car diovascular disease is currently tentative, the evidence being accumulated to suggest that CYP pathways are altered in animal models of hypertension a nd atherosclerosis can no longer be ignored. The development of selective p harmacological tools is, however, a prerequisite for the analysis of the in volvement of specific CYP isoforms in the regulation of vascular homeostasi s in human subjects.