© 1997 American Heart Association, Inc.
Articles |
Mechanism of Vascular Smooth Muscle Relaxation by Estrogen in Depolarized Rat and Mouse Aorta
Role of Nuclear Estrogen Receptor and Ca2+ Uptake
From the Cardiovascular Research Department (A.D.F., G.M.R.), Berlex Biosciences, Richmond, Calif, and the Laboratory of Reproductive and Developmental Toxicology (S.W.C., K.S.K.), National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC.
Correspondence to Gabor M. Rubanyi, MD, PhD, Berlex Biosciences, Cardiovascular Research, 15049 San Pablo Ave, Richmond, CA 94804. E-mail rubanyi_gabor{at}berlex.com
Abstract 17ß-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 Ca2+ in
17ß-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
NG-nitro-L-arginine, 17ß-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
17ß-estradiol–induced relaxations. 125I-17ß-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. 17ß-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,
17ß-estradiol inhibited the increase of 45Ca uptake by
30 mmol/L KCl at concentrations (10 and 30 µmol/L) that
caused vasorelaxation in the same tissue, suggesting that inhibition of
Ca2+ entry contributes to the response. 17
-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.
Key Words: 17ß-estradiol • 17-estradiol • estrone • diethylstilbestrol • mice, estrogen receptor–deficient
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