Estrogen-mediated cytoplasmic and nuclear distribution of rat cardiovascular estrogen receptors.

Abstract

We used either the synthetic estrogen R2858 (moxestrol) or estradiol-17(3 to characterize estrogen receptors in cytoplasmic (R2858) and nuclear (estradiol-17B) preparations from rat aorta and myocardium. Relative steroid specificity studies showed that only estrogens were effective inhibitors of R2858 or estradiol-171) binding to aortic and myocardial estrogen receptors, whereas androgens, progestins, and cortisol were ineffective inhibitors. Low ionic strength sucrose density gradient analyses showed that myocardial estrogen receptors that localized in the cytoplasmic fraction migrated as macromolecules with sedimentation coefficients of 8S to 9S. In contrast, two binding components of sedimentation coefficients 8S to 9S and 10S to 11S were characteristic of the estrogen receptors localized in aortic cytoplasmic preparations. High ionic strength sucrose density gradient analysis showed that aortic and myocardial estrogen receptors localized in the nuclear fraction migrated as macromolecules with sedimentation coefficients of 4S to 6S. Saturation analyses showed that aortic and myocardial cytoplasmic preparations from intact young mature male rats contained 50.6 ± 12.9 (mean ± SD) and 51.0 ± 14.1 fmol receptor/mg DNA, respectively. The respective R2858 dissociation constants were 0.42 and 0.15 nM. Estrogen receptors could not be demonstrated in nuclear preparations from cardiovasculature of intact males. Estradiol-17(3 injection of intact young mature male rats caused "depletion" of aortic and myocardial cytoplasmic fraction estrogen receptors and resulted in the appearance of 51.9 ± 21.0 and 36.9 ± 9.5 fmol receptor/mg DNA in the corresponding nuclear fractions. The respective estradiol-17(3 dissociation constants were 1.56 and 0.71 nM. Increased estrogen receptor content of cardiovascular nuclear fractions of estradiol-17(3 injected male rats correlated well with the concomitant decreased cytoplasmic fraction receptor content. The ability of estradiol-17(3 to affect localization of cardiovascular estrogen receptors between cytoplasmic and nuclear fractions suggests these estrogen receptors are physiologically functional and indicates that estrogen may directly regulate cardiovascular cell function. (Arteriosclerosis 5:668-677, November/December 1985)T he higher incidence of coronary heart disease (CHD) in postmenopausal women as compared to premenopausal individuals 12 and in oral contraceptive users as compared to nonusers 23 and the decreased mortality of estrogen-only users as compared to nonusers 2 -"• 5 has suggested a possible Received December 17,1984; revision accepted July 10,1985. etiologic role for estrogens in CHD. This impression is supported by reports of higher plasma estrogen content in males who survived a myocardial infarction 6 " 11 or have documented coronary artery occlusion in the absence of an infarction. 8 ' 9 These clinical observations have led some investigators to conclude that hyperestrogenemia is an additional risk factor for CHD in males. 6810

Gender Differences in Ca 2+ Entry Mechanisms of Vasoconstriction in Wistar-Kyoto and Spontaneously Hypertensive Rats

“…Since the expression of sex hormone receptors in arterial smooth muscle may vary depending on the gender and the status of the gonads, 20 the observed gender differences in the vascular reactivity to estrogen may well be related to the relative abundance of estrogen receptors. This is supported by reports that estrogen receptors have been identified in the rat aorta [21][22][23] and that females have higher levels of estrogen receptors in their arteries than males. 24 However, the gender differences may also be related to differences in the signaling mechanisms downstream from receptor activation.…”

Postexercise α-adrenergic receptor hyporesponsiveness in hypertensive rats is due to nitric oxide

“…Specifically, the observed sex differences in the AP response to exercise may be related to the relative abundance of estrogen and estrogen receptors. This concept is supported by the observation that females have a higher density of estrogen receptors in their arteries than males (8,39,41). Furthermore, estrogen is known to affect vascular tone by modulating the release of endothelium-derived vasoactive factors (19).…”

“…In addition, estrogen mediates vasodilation in deendothelialized vessels, suggesting an endothelium-independent vasodilation component that involves a direct action on vascular smooth muscle (10). Estrogen receptors have been identified in vascular smooth muscle cells, and specific binding sites have been demonstrated on the endothelium (39,41). Estrogen administration promotes vasodilation both in human and experimental animals, in part, by stimulating prostacyclin and NO synthesis (15).…”

Effect of Estrogen Replacement on Vasoconstrictor Responses in Rat Mesenteric Arteries

“…1,2 This is believed to be due to the protective effect of circulating estrogen because estrogen replacement therapy significantly reduces the incidence of cardiovascular disorders in postmenopausal women. 3,4 The vascular wall has been shown to contain specific high-affinity receptors for estrogen both in humans 5,6 and in animals, [7][8][9] providing strong biological evidence that the cardiovascular system is one of the targets of estrogen. However, the exact mechanisms of the protective effect of estrogen are still unknown.…”