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NEUROHUMORAL CONTROL OF CARDIOVASCULAR FUNCTION

Contribution of epoxyeicosatrienoic acids to flow-induced dilation in arteries of male ER knockout mice: role of aromatase

Departments of ¹Physiology and ²Pharmacology, New York Medical College, Valhalla, New York; and ³Jiangsu Province Key Laboratory of Anesthesiology, Department of Physiology, Xuzhou Medical College, Xuzhou, Jiangsu, China

Submitted 13 March 2007 ; accepted in final form 16 July 2007

We studied the roles of estrogen receptors (ER) and aromatase in the mediation of flow-induced dilation (FID) in isolated arteries of male ER-knockout (ER-KO) and wild-type (WT) mice. FID was comparable between gracilis arteries of WT and ER-KO mice. In WT arteries, inhibition of NO and prostaglandins eliminated FID. In ER-KO arteries, N-nitro-L-arginine methyl ester (L-NAME) inhibited FID by 26%, whereas indomethacin inhibited dilations by 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/cm² shear stress, perfusate passing through donor vessels isolated from gracilis muscle of ER-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 ER-KO compared with WT mice. Western blot analysis showed a significantly reduced endothelial nitric oxide synthase expression but enhanced expressions of aromatase and ER in ER-KO arteries. Treatment of ER-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 ER-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.

estradiol; testosterone; receptors; nitric oxide; endothelium-derived hyperpolarizing factor