To move or not to move? Cytochrome P450 products and cell migration.

Over the last 5 to 8 years, researchers have begun to appreciate the prominent role played by cytochrome P450 (CYP) enzymes in the regulation of vascular tone, homeostasis, and blood pressure. For example, interfering with CYP genes markedly affects blood pressure in mice,1 and numerous reports have demonstrated that CYP expression is altered in genetic and experimental models of hypertension (for a recent review, see Moreno et al2). Vascular CYP enzymes can be divided into two classes, the epoxygenases, which metabolize arachidonic acid to a series of regiospecific and stereospecific epoxides (5,6-, 8,9-, 11,12and 14,15-epoxyeicosatrienoic acids or EETs), which are potent vasodilators, and the -hydroxylases, which generate the vasoconstrictor eicosanoid, 20-hydroxyeicosatetraenoic acid (20-HETE). 20-HETE is thought to mediate the myogenic response as well as the contraction induced by a number of contractile agonists and is generally assumed to augment basal blood pressure.3 EETs, on the other hand, are potent vasodilators and play a central role in the nitric oxide– and prostacyclin-independent relaxation of coronary, renal, and cerebral arteries. Although identified as potential endothelium-derived hyperpolarizing factors (EDHFs), it is now appreciated that EETs regulate much more than vascular tone and are in fact intracellular signal transduction molecules that have a central function in the regulation of vascular homeostasis.4 The effects of EETs can be attributed to their ability to activate a number of signal transduction pathways (in addition to those responsible for the activation of Ca -dependent K channels and hyperpolarization) in endothelial as well as vascular smooth muscle cells (Figure). A number of intracellular EET effectors have been identified and include tyrosine kinases and phosphatases, mitogen-activated protein kinases (ERK1/2, p38 MAPK, and the c-Jun N-terminal kinase), the EGF receptor tyrosine kinase, phosphatidylinositol-3 kinase, protein kinase B/Akt, ADP ribosyl transferases, the I B kinase, and adenylyl cyclase (for review, see Roman5). EETs, in particular 11,12-EET, also seem to possess antiinflammatory properties, because the exogenous application of EETs to TNF -stimulated mice or endothelial cells prevents the activation of NFB and the expression of vascular cell adhesion molecule-1 (VCAM-1).6,7 As EETs are generated within endothelial and smooth muscle cells, it is tempting to suggest that enhancing the vascular production of these antiinflammatory eicosanoids may protect against vascular disease. There is in fact strong circumstantial evidence supporting this hypothesis. Interventions that prevent the further metabolism of EETs to the respective dihydroxyeicosatrienoic acids by the soluble epoxide hydrolase inhibit PDGF-induced smooth muscle cell proliferation8 and have been associated with beneficial changes in blood pressure in spontaneously hypertensive rats9 as well as in animals treated with angiotensin II.10 Enhancing CYP expression and EET generation, on the other hand, are reported to protect against apoptosis11 as well as the injury induced by hypoxia and reoxygenation.12 In this issue of Circulation Research, Sun et al13 report that EETs affect cellular processes involved in smooth muscle cell migration and show that 11,12-EET can inhibit the PDGFinduced migration of rat aortic smooth muscle cells. The effector pathway involved in this response, like the EETmediated vasodilatation of afferent arterioles,14 induction of tissue-type plasminogen activator gene transcription,15 and increase in interendothelial gap junctional communication,16 requires the activation of adenylyl cyclase, accumulation of cAMP, and activation of protein kinase A. However, in contrast to the effects of most autacoids on cyclic nucleotide production, the activation of adenylyl cyclase by 11,12-EET was prolonged, and intracellular levels of cAMP remained elevated for at least 4 hours. Despite the pronounced effects on cAMP levels, Sun et al were unable to detect any effect of 11,12-EET on smooth muscle cell proliferation, a finding that contrasts with a recent report that EETs as well as an inhibitor of the soluble epoxide hydrolase effectively prevented the PDGF-stimulated proliferation and expression of cyclin D1 in human fibroblasts and coronary artery smooth muscle cells.8 The antimigratory effects observed by Sun et al13 in response to the application of exogenously applied EET were much more marked than those detected in cells overexpressing the EET-generating epoxygenase CYP 2J2. The latter observation could be explained by the fact that the CYP 2J2 enzyme does not generate only 11,12-EET but rather a spectrum of EETs. Indeed, Sun et al report that the antimigratory effects of 5,6and 14,15-EET were markedly less potent than those of 11,12-EET. However, because EET production in the CYP 2J2–overexpressing cells used was not assessed, it is impossible to exclude the possibility that other CYP metabolites and/or EET metabolites contribute to or interfere with the effects of 11,12-EET. The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Institut für Kardiovaskuläre Physiologie, Klinikum der J.W.G.-Universität, Frankfurt am Main, Germany. Correspondence to Ingrid Fleming, Institut für Kardiovaskuläre Physiologie, Klinikum der J.W.G.-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany. (Circ Res. 2002;90:936-938.) © 2002 American Heart Association, Inc.