Mechanism of Vascular Smooth Muscle Relaxation by Estrogen in Depolarized Rat and Mouse Aorta

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Abstract
17β-Estradiol induces vasodilation in vitro and in vivo, which has been suggested to contribute to the cardiovascular protection by this ovarian steroid hormone. However, the exact mechanism of vasorelaxation by estrogens remains to be elucidated. In this study, we analyzed the potential role of genomic mechanisms involving the nuclear estrogen receptor and inhibition of entry of extracellular Ca 2+ in 17β-estradiol–induced vasorelaxation in depolarized aortic rings, isolated from male and female rats and male mice. In both male and female rat aortic rings without endothelium and in intact male mouse aortic rings treated with N G -nitro- l -arginine, 17β-estradiol caused dose-dependent (0.3 to 30 μmol/L) relaxation of contraction evoked by high-K + depolarization (30 and 45 mmol/L KCl, respectively). The estrogen receptor antagonist ICI 164384 had no effect on 17β-estradiol–induced relaxations. 125 I-17β-estradiol binding studies showed the presence of high-affinity cytosolic-nuclear estrogen receptors in control male mouse aortas. Comparable relaxations of aortic rings isolated from control and estrogen receptor–deficient transgenic mice provided direct evidence that the nuclear estrogen receptor is not involved in this response. 17β-Estradiol–induced relaxation of rat aortic rings could not be prevented by cycloheximide or actinomycin D, suggesting that the response was not mediated by de novo protein synthesis or gene transcription. In rat aortic rings, 17β-estradiol inhibited the increase of 45 Ca uptake by 30 mmol/L KCl at concentrations (10 and 30 μmol/L) that caused vasorelaxation in the same tissue, suggesting that inhibition of Ca 2+ entry contributes to the response. 17α-Estradiol was less effective, and estrone was devoid of vasorelaxing activity. Vasorelaxation by estrogens in female and male rat aortas was similar, indicating no gender difference in vascular responses under these conditions.