Genomic and nongenomic effects of estrogen in the vasculature1

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Abstract

Estrogen has both rapid vasodilatory effects and longer-term effects on the vasculature. The longer-term effects of estrogen are produced, at least in part, by changes in vascular cell gene and protein expression that are mediated by the ligand-activated transcription factors, estrogen receptor (ER)-α and ER-β. The rapid vasodilatory effects of estrogen do not require changes in gene expression and are produced by estrogen-stimulated increases in endothelial cell nitric oxide synthase activity. This results in nitric oxide-mediated increases in cyclic guanosine monophosphate in vascular smooth muscle cells, which mediate vasodilatation. This article briefly reviews recent progress in this field of vascular biology.

Section snippets

Genomic effects

The ERs, as with all members of the nuclear hormone receptor superfamily, are ligand-activated transcription factors. Expression of either or both of these receptors defines those tissues that are targets of estrogen action. Although both receptors are expressed in vascular endothelial and smooth muscle cells, some data show that ERβ expression predominates in endothelial cells, whereas ERα expression is greater in smooth muscle cells. However, the overall level of expression of ERα and ERβ in

Nongenomic effects

Estrogen can increase the bioavailability of endothelially derived nitric oxide in a variety of models.6, 7 When administered directly into a coronary artery of a nonhuman primate or a human, estradiol causes rapid vasodilatation by activating endothelial nitric oxide production.6 The molecular mechanism(s) by which estrogen activates eNOS is an area of intense current interest and remains controversial. The remainder of this article reviews recent progress in elucidating the estrogen-ER-eNOS

Estrogen and the atherosclerotic process

Estrogen has atheroprotective actions in both normolipidemic and hypercholesterolemic animal models. Estradiol protects against vascular injury in mice generated in Chapel Hill, North Carolina (knockout [KO]CH mice), which harbor disruptions of ERα or ERβ.6 The most recent data on this issue emerge from the study of the genetic cross of these 2 animals. ERα,ERβ (double)KOCH mice lose the protection of estrogen against some, but not all, vascular injury endpoints.15 These data raised the

Conclusion

Vascular cells express functional ERα and ERβ. Both the longer-term vascular effects of estrogen and rapid vasodilatation in response to estrogen are mediated by these receptors. Data indicate that the rapid response occurs in caveolae of endothelial cells and does not require new gene expression. Molecular pathways for estrogen-mediated rapid vasodilatation and the physiologic significance of estrogen-mediated vasodilatation are not fully understood. Longer-term effects of estrogen to protect

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Cited by (0)

1

Discussion of unlabeled use of products: Estrogens are not labeled for any effects they may have on the cardiovascular system or for the treatment of cardiovascular disease.

2

Disclosure: Dr. Mendelsohn does not have a financial interest or other relationship with any manufacturer or commercial product.

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