Vasorelaxant action of 17 -estradiol in rat uterine arteries: role of nitric oxide synthases and estrogen receptors

1 Centre de Recherche, Centre Hospitalier Universitaire Sainte-Justine, and Departments of 2 Obstetrics and Gynecology and 3 Pharmacology, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada Submitted 26 June 2007 ; accepted in final form 15 October 2007 The uterine vasculature plays an important role during pregnancy by providing adequate perfusion of the maternal-fetal interface. To this end, substantial remodeling of the uterine vasculature occurs with consequent changes in responsiveness to contractile agents. The purpose of our study was to characterize the vasorelaxant effects of estrogens on vascular smooth muscles of the rat uterine artery during pregnancy and to evaluate the involvement of estrogen receptors (ESR) and nitric oxide synthases (NOS). To do so, we measured NOS expression in the whole uterine and mesenteric circulatory bed by Western blotting. Vasorelaxant effects of 17β-estradiol (17β-E 2 ) were assessed on endothelium-denuded uterine arteries with wire myographs in the absence and presence of pharmacological modulators [nitro- L -arginine methyl ester ( L -NAME), ICI-182780, tamoxifen]. All experiments were performed on arteries from nonpregnant (NP) and late pregnant (P) rats. In the uterine vasculature of the latter group, NOS3 (endothelial NOS) expression was increased, while NOS1 (neuronal NOS) was reduced compared with NP rats. Expression of the NOS2 (inducible NOS) isoform was undetectable in the two groups. Both 17β-E 2 and 17 -E 2 induced uterine artery relaxation, but the latter evoked lower responses. Endothelium-denuded arteries from NP rats showed larger relaxation with 17β-E 2 than P rats. This larger relaxation disappeared in the presence of L -NAME. The ESR antagonist ICI-182780 did not affect acute relaxation with 17β-E 2 and 17 -E 2 . Moreover, membrane-nonpermeant 17β-E 2 :BSA (estradiol conjugated to bovine serum albumin) did not induce any vasorelaxation. Our results indicate that estrogens exert direct acute vasorelaxant effects in smooth muscles of the rat uterine artery that are mediated by mechanisms independent of ESR activation, but with some stereospecificity. Part of this effect, in NP rats only, is due to nitric oxide produced from muscle NOS1. estrogens; pregnancy Address for reprint requests and other correspondence: J. St-Louis, Centre de Recherche, CHU Sainte-Justine, 3175 Chemin Côte-Sainte-Catherine, Montreal, QC, Canada H3T 1C5 (e-mail: jean.st-louis{at}umontreal.ca )