Published online before print December 11, 2003, doi: 10.1161/01.RES.0000111525.96232.46
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Submitted on July 1, 2003
Revised on November 19, 2003
Accepted on November 21, 2003
Estrogen Elicits Cytochrome P450-Mediated Flow-Induced Dilation of Arterioles in NO Deficiency. Role of PI3K-Akt Phosphorylation in Genomic Regulation
An Huang *;
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.
* To whom correspondence should be addressed. 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 NG-nitro-L-arginine methyl ester (L-NAME)-treated male and ovariectomized female rats before and after overnight incubation with 17
-estradiol (17-E2, 10-9 mol/L). In control conditions, prostaglandins (PGs) mediated FID, because indomethacin (INDO) abolished the responses. After incubation of the vessels with 17-E2, the basal tone of arterioles was significantly reduced and FID was augmented. INDO did not affect the dilation of the vessels incubated with 17-E2. Dilations of these vessels, however, were eliminated by PPOH and miconazole, inhibitors of CYP/epoxygenase. Simultaneous incubation of the vessels with 17-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 with17-E2. Western blot analysis indicated a significantly increased phospho-Akt level in arterioles incubated with 17-E2 compared with those without 17-E2. The enhanced phospho-Akt in response to 17-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 17-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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