PMID- 14670845 OWN - NLM STAT- MEDLINE DCOM- 20040426 LR - 20211203 IS - 1524-4571 (Electronic) IS - 0009-7330 (Print) IS - 0009-7330 (Linking) VI - 94 IP - 2 DP - 2004 Feb 6 TI - Estrogen elicits cytochrome P450--mediated flow-induced dilation of arterioles in NO deficiency: role of PI3K-Akt phosphorylation in genomic regulation. PG - 245-52 AB - 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 17beta-estradiol (17beta-E2, 10(-9) mol/L). In control conditions, prostaglandins (PGs) mediated FID, because indomethacin (INDO) abolished the responses. After incubation of the vessels with 17beta-E2, the basal tone of arterioles was significantly reduced and FID was augmented. INDO did not affect the dilation of the vessels incubated with 17beta-E2. Dilations of these vessels, however, were eliminated by PPOH and miconazole, inhibitors of CYP/epoxygenase. Simultaneous incubation of the vessels with 17beta-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 with 17beta-E2. Western blot analysis indicated a significantly increased phospho-Akt level in arterioles incubated with 17beta-E2 compared with those without 17beta-E2. The enhanced phospho-Akt in response to 17beta-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 17beta-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. FAU - Huang, An AU - Huang A AD - Department of Physiology, New York Medical College, Valhalla, NY 10595, USA. an_huang@nymc.edu FAU - Sun, Dong AU - Sun D FAU - Wu, Zhiping AU - Wu Z FAU - Yan, Changdong AU - Yan C FAU - Carroll, Mairead A AU - Carroll MA FAU - Jiang, Houli AU - Jiang H FAU - Falck, John R AU - Falck JR FAU - Kaley, Gabor AU - Kaley G LA - eng GR - R01 HL070653-02/HL/NHLBI NIH HHS/United States GR - HL 68813/HL/NHLBI NIH HHS/United States GR - R01 HL068813/HL/NHLBI NIH HHS/United States GR - HL 070653/HL/NHLBI NIH HHS/United States GR - P01 HL034300/HL/NHLBI NIH HHS/United States GR - P01 HL043023/HL/NHLBI NIH HHS/United States GR - R01 HL070653/HL/NHLBI NIH HHS/United States GR - HL 43023/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, U.S. Gov't, P.H.S. DEP - 20031211 PL - United States TA - Circ Res JT - Circulation research JID - 0047103 RN - 0 (6-(2-propargyloxyphenyl)hexanoic acid) RN - 0 (Androstadienes) RN - 0 (Caproates) RN - 0 (Enzyme Inhibitors) RN - 0 (Phosphoinositide-3 Kinase Inhibitors) RN - 0 (Proto-Oncogene Proteins) RN - 22X328QOC4 (Fulvestrant) RN - 31C4KY9ESH (Nitric Oxide) RN - 4TI98Z838E (Estradiol) RN - 7NNO0D7S5M (Miconazole) RN - 9035-51-2 (Cytochrome P-450 Enzyme System) RN - EC 2.7.11.1 (Akt1 protein, rat) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - V55S2QJN2X (NG-Nitroarginine Methyl Ester) RN - XVA4O219QW (Wortmannin) RN - XXE1CET956 (Indomethacin) SB - IM MH - Androstadienes/pharmacology MH - Animals MH - Arterioles/*drug effects/enzymology MH - Caproates/pharmacology MH - Cytochrome P-450 Enzyme System/biosynthesis/genetics/*physiology MH - Endothelium, Vascular/drug effects/metabolism MH - Enzyme Induction/drug effects/physiology MH - Enzyme Inhibitors/pharmacology MH - Estradiol/*analogs & derivatives/*pharmacology MH - Female MH - Fulvestrant MH - *Hemorheology MH - Indomethacin/pharmacology MH - Male MH - Miconazole/pharmacology MH - NG-Nitroarginine Methyl Ester/pharmacology MH - Nitric Oxide/*deficiency MH - Phosphatidylinositol 3-Kinases/*physiology MH - Phosphoinositide-3 Kinase Inhibitors MH - Phosphorylation MH - Protein Processing, Post-Translational/drug effects/*physiology MH - *Protein Serine-Threonine Kinases MH - Proto-Oncogene Proteins/antagonists & inhibitors/*physiology MH - Proto-Oncogene Proteins c-akt MH - Rats MH - Rats, Wistar MH - Signal Transduction/drug effects/physiology MH - Stress, Mechanical MH - Transcription, Genetic/drug effects MH - Vasodilation/*drug effects/physiology MH - Wortmannin PMC - PMC4536912 MID - NIHMS335845 EDAT- 2003/12/13 05:00 MHDA- 2004/04/27 05:00 PMCR- 2015/08/14 CRDT- 2003/12/13 05:00 PHST- 2003/12/13 05:00 [pubmed] PHST- 2004/04/27 05:00 [medline] PHST- 2003/12/13 05:00 [entrez] PHST- 2015/08/14 00:00 [pmc-release] AID - 01.RES.0000111525.96232.46 [pii] AID - 10.1161/01.RES.0000111525.96232.46 [doi] PST - ppublish SO - Circ Res. 2004 Feb 6;94(2):245-52. doi: 10.1161/01.RES.0000111525.96232.46. Epub 2003 Dec 11.