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(Circulation Research. 2004;94:245.)
© 2004 American Heart Association, Inc.

Integrative Physiology

Estrogen Elicits Cytochrome P450—Mediated Flow-Induced Dilation of Arterioles in NO Deficiency

Role of PI3K-Akt Phosphorylation in Genomic Regulation

An Huang, Dong Sun, Zhiping Wu, Changdong Yan, Mairead A. Carroll, Houli Jiang, John R. Falck, Gabor Kaley

From the Departments of Physiology (A.H., D.S., Z.W., C.Y., G.K.) and Pharmacology (M.A.C., H.J.), New York Medical College, Valhalla, NY; and the Department of Biochemistry (J.R.F.), University of Texas, Southwestern Medical Center, Dallas, Tex.

Correspondence to An Huang, MD, PhD, Department of Physiology, New York Medical College, Valhalla, NY 10595. E-mail an_huang{at}nymc.edu

This study investigated the mechanisms responsible for the estrogen-dependent, cytochrome P450 (CYP)-mediated dilator responses to shear stress in arterioles of NO-deficient female rats and mice. Flow-induced dilation (FID) was assessed in isolated arterioles from N^G-nitro-L-arginine methyl ester (L-NAME)-treated male and ovariectomized female rats before and after overnight incubation with 17ß-estradiol (17ß-E₂, 10^-9 mol/L). In control conditions, prostaglandins (PGs) mediated FID, because indomethacin (INDO) abolished the responses. After incubation of the vessels with 17ß-E₂, the basal tone of arterioles was significantly reduced and FID was augmented. INDO did not affect the dilation of the vessels incubated with 17ß-E₂. Dilations of these vessels, however, were eliminated by PPOH and miconazole, inhibitors of CYP/epoxygenase. Simultaneous incubation of the vessels with 17ß-E₂ plus ICI, 182,780, an estrogen receptor antagonist, or wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI3K) phosphorylation or the transcriptional inhibitor DRB, prevented the reduced arteriolar tone and the enhanced CYP-mediated FID caused by incubation of vessels with17ß-E₂. Western blot analysis indicated a significantly increased phospho-Akt level in arterioles incubated with 17ß-E₂ compared with those without 17ß-E₂. The enhanced phospho-Akt in response to 17ß-E₂ was localized, by immunohistochemistry, to arteriolar endothelial cells. Moreover, GC-MS analysis indicated a significantly increased production of epoxyeicosatrienoic acids, vasodilator metabolites of CYP/epoxygenase, in arterioles incubated with 17ß-E₂, a response that was prevented by ICI 182780 and wortmannin, respectively. Thus, estrogen, via a receptor-dependent, PI3K/Akt-mediated pathway, transcriptionally upregulates CYP activity, leading to an enhanced arteriolar response to shear stress.

Key Words: estradiol • flow-induced dilation • cytochrome P450 • Akt • transcription

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