Estrogen Receptor-α Mediates the Protective Effects of Estrogen Against Vascular Injury

Abstract

Abstract-Blood vessel cells express the 2 known estrogen receptors, ␣ and ␤ (ER␣, ER␤), which are thought to mediate estrogen inhibition of vascular injury and atherosclerosis, but the relative role of ER␣ and ER␤ in these events is controversial. Key Words: estrogen Ⅲ hormones Ⅲ vascular injury Ⅲ receptors Ⅲ animal models T he cardiovascular effects of steroid hormones are an area of intense interest at present. Estrogen has known systemic effects on circulating factors and has more recently been established to have direct effects on the blood vessel wall. Estrogen causes both rapid vascular dilatation and longer-term effects on gene expression in vascular cells (reviewed in Mendelsohn and Karas 1 ). At physiologically relevant concentrations of estrogen, studies support that estrogen receptors (ERs) ␣ and ␤ mediate both the rapid and the long-term cardiovascular effects of estrogen. ER␣ and ER␤ are expressed in both vascular endothelial and smooth muscle cells, but their physiological roles in the vasculature are incompletely understood.Using wild-type and estrogen receptor knockout mice, we have previously studied the role of ER␣ and ER␤ in mediating the vascular protective effects of estrogen in a mouse carotid artery injury model. 2,3,5,6 Studies of mice harboring single gene deletions of either ER␣ or ER␤ showed that treatment of ovariectomized female mice with nanomolar concentrations of 17␤-estradiol (E 2 ) inhibits the response to vascular injury to equivalent levels in wild-type mice, ER␣KO Chapel Hill (ER␣KO CH ) and ER␤KO CH . 2,5 These findings suggested that ER␣ and ER␤ are able to complement one another such that each receptor alone is sufficient to mediate the vascular protective effects of estrogen, or that the vascular protective effects of estrogen are mediated by an ER␣/ER␤-independent pathway. To distinguish between these 2 hypotheses, studies of vascular injury in ER␣,␤KO CH (double) estrogen receptor knockout mice were performed. 6 However, the effect of estrogen on vascular injury in these mice was complex. Although E 2 no longer inhibited the increases in medial carotid area after injury in the ER␣,␤KO CH mice, E 2 still significantly inhibited vascular smooth muscle cell (VSMC) proliferation after injury. In addition, E 2 also caused a significant increase in uterine weight in the ER␣,␤KO CH mice. 6 These data showed that the role of estrogen receptors could diverge for specific components of the vascular injury response in the ER␣,␤KO CH mice. However, the results left unresolved what is responsible for estrogen inhibition of VSMC proliferation and the increase in uterine weight in the ER␣,␤KO CH mice. These could be due to an unidentified third estrogen receptor or to residual function of protein from an ER␣ splice variant known to be expressed in the parental ER␣KO CH mice. 7 To resolve the question as to how estrogen Original

Sex differences in angiotensin II- induced hypertension

“…Crucial roles for ERα in the protection against vascular injury, activation of endothelial NO synthase (NOS) and anti-atherosclerotic effects have been amply documented (28,29). Genetic deletion of ERß results in the development of hypertension in middle-aged female and male mice due to multiple abnormalities of ion channel function in blood vessels (30).…”

Truncated Estrogen Receptor α 46-kDa Isoform in Human Endothelial Cells

“…Indeed, the vascular responses to estrogen that are preserved in these ␣ERKO mice 8 are abolished in a new knockout mouse with total deletion of ER␣ gene. [21][22][23] Specifically, expression of alternatively spliced transcripts lacking the AF-1 domain in ␣ERKO mice seems to mediate estrogen-induced endothelial NO production that is absent in the complete knockout. 24 These insights from mouse models suggest that mouse homologs of ⌬1a-hER␣-46 are sufficient to mediate the acute endothelial effects of estrogen and in principle support our observations of the functional effects of hER␣-46 in human endothelial cells, although the 46-kDa truncated ER␣ protein was not readily detected in mouse aortic lysates.…”

Haplotype-Based Case-Control Study of Estrogen Receptor α (ESR1) Gene and Pregnancy-Induced Hypertension

“…Although estrone and estradiol levels increase 100 times and estriol levels increase 1,000 times during pregnancy, blood pressure remains within the normal range during normal pregnancy ( 27 ). The estrogen receptor ESR1 activates specific target genes in vascular smooth muscle, inhibits smooth muscle cell migration, and accelerates endothelial cell growth in vitro and in vivo ( 13 ). In addition, fewer ESR1 molecules are found in premenopausal women with atherosclerotic coronary arteries than in those with normal arteries ( 11 , 12 ).…”