Estrogen elicits cytochrome P450--mediated flow-induced dilation of arterioles in NO deficiency: role of PI3K-Akt phosphorylation in genomic regulation.
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.
Huang
An
A
Department of Physiology, New York Medical College, Valhalla, NY 10595, USA. an_huang@nymc.edu
Sun
Dong
D
Wu
Zhiping
Z
Yan
Changdong
C
Carroll
Mairead A
MA
Jiang
Houli
H
Falck
John R
JR
Kaley
Gabor
G
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001160:Arterioles / Q000187:drug effects* / Q000201:enzymology; D002208:Caproates / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005260:Female; D000077267:Fulvestrant; D018056:Hemorheology; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D008825:Miconazole / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000172:deficiency*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013314:Stress, Mechanical; D014158:Transcription, Genetic / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D000077191:Wortmannin
D000730:Androstadienes; D002208:Caproates; D003577:Cytochrome P-450 Enzyme System; D004791:Enzyme Inhibitors; D004958:Estradiol; D000077267:Fulvestrant; D007213:Indomethacin; D008825:Miconazole; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin; C121755:6-(2-propargyloxyphenyl)hexanoic acid; C494920:Akt1 protein, rat