title: Contribution of epoxyeicosatrienoic acids to flow-induced dilation in arteries of male ERalpha knockout mice: role of aromatase.
abstract: We studied the roles of estrogen receptors (ER) and aromatase in the mediation of flow-induced dilation (FID) in isolated arteries of male ERalpha-knockout (ERalpha-KO) and wild-type (WT) mice. FID was comparable between gracilis arteries of WT and ERalpha-KO mice. In WT arteries, inhibition of NO and prostaglandins eliminated FID. In ERalpha-KO arteries, N(omega)-nitro-L-arginine methyl ester (L-NAME) inhibited FID by approximately 26%, whereas indomethacin inhibited dilations by approximately 50%. The remaining portion of the dilation was abolished by additional administration of 6-(2-proparglyoxyphenyl)hexanoic acid (PPOH) or iberiotoxin, inhibitors of epoxyeicosatrienoic acid (EET) synthesis and large-conductance potassium channels, respectively. By using an electrophysiological technique, we found that, in the presence of 10 dyne/cm(2) shear stress, perfusate passing through donor vessels isolated from gracilis muscle of ERalpha-KO mice subjected to L-NAME and indomethacin elicited smooth muscle hyperpolarization and a dilator response of endothelium-denuded detector vessels. These responses were prevented by the presence of iberiotoxin in detector or PPOH in donor vessels. Gas chromatography-mass spectrometry (GC-MS) analysis indicated a significant increase in arterial production of EETs in ERalpha-KO compared with WT mice. Western blot analysis showed a significantly reduced endothelial nitric oxide synthase expression but enhanced expressions of aromatase and ERbeta in ERalpha-KO arteries. Treatment of ERalpha-KO arteries with specific aromatase short-interfering RNA for 72 h, knocked down the aromatase mRNA and protein associated with elimination of EET-mediation of FID. Thus, FID in male ERalpha-KO arteries is maintained via an endothelium-derived hyperpolarizing factor/EET-mediated mechanism compensating for reduced NO mediation due, at least in part, to estrogen aromatized from testosterone.
authors.affiliation: Department of Physiology, New York Medical College, Valhalla, NY 10595, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Sun
authors.forename: Changdong
authors.initials: C
authors.lastname: Yan
authors.forename: Azita
authors.initials: A
authors.lastname: Jacobson
authors.forename: Houli
authors.initials: H
authors.lastname: Jiang
authors.forename: Mairead A
authors.initials: MA
authors.lastname: Carroll
authors.forename: An
authors.initials: A
authors.lastname: Huang
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001141:Aromatase / Q000502:physiology*; D001158:Arteries / Q000502:physiology*; D015153:Blotting, Western; D047628:Estrogen Receptor alpha / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D008401:Gas Chromatography-Mass Spectrometry; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000201:enzymology / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D010477:Perfusion; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013314:Stress, Mechanical; D014664:Vasodilation / Q000235:genetics* / Q000502:physiology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D047628:Estrogen Receptor alpha; D009943:Organophosphorus Compounds; D010455:Peptides; D034741:RNA, Small Interfering; C074765:propenylphosphonic acid; C064719:iberiotoxin; D052250:Nitric Oxide Synthase Type III; D001141:Aromatase; D015126:8,11,14-Eicosatrienoic Acid; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin