Protective effects of estrogen on the cardiovascular system☆
Section snippets
Estrogen receptors
Jensen and Jacobson2 and Toft and Gorski3 first described the ER in the 1960s. In 1985, this receptor became the second member of the steroid hormone-receptor superfamily to be cloned.4 For a decade thereafter, extensive searching for a second ER was unsuccessful. In 1996, Kuiper et al5 reported cloning of the second ER and named it ER-β, designating the first identified ER as ER-α.5 Both ER-α and ER-β are expressed in vascular cells and tissues.6
The effects of estrogen are mediated through
Animal studies on the role of estrogen receptors in vascular injury response
Animal models of carotid injury have been useful for examining the role of ER-α and ER-β in mediating the vascular response to injury, as measured by increases in medial wall area (thickness) and proliferation of smooth muscle cells. In this model, ovariectomized female mice receive either placebo or 17β-estradiol to achieve steady-state physiologic levels of estrogen by implantation of a time-release pellet containing the compound. Passing a fine wire into the common carotid artery induces
ER-α KO mice study
In the first study,7 uninjured carotid arteries from WT and ER-α KO mice (generated in Chapel Hill, North Carolina),8 were found to be morphometrically and immunohistochemically indistinguishable. In the injured carotid arteries, the carotid medial area increased significantly compared with uninjured vessels in both the WT (p <0.05) and ER-α KO (p <0.05) mice (Figure 2, left). Treatment with 17β-estradiol inhibited this response in both the WT and ER-α KO mice, whereas in both types of mice,
Direct vascular effects of estrogen
The direct actions of estrogen on the cardiovascular system include rapid nongenomic effects and longer term effects that involve changes in gene expression (Table 1). It is estimated that the direct effects of estrogen on the vasculature account for the majority of its cardioprotective effects, although there are insufficient data at present to be certain of this.10
Indirect vascular effects of estrogen
In addition to its direct effects on cardiovascular function, estrogen has an indirect influence on serum lipid concentrations, coagulation and fibrinolytic systems, antioxidant effects, and the production of other vasoactive compounds (Table 1).1 Most of these effects involve receptor-mediated effects on hepatic expression of specific genes, such as apoprotein genes or genes for coagulation and fibrinolytic enzymes.
Orally administered estrogen is associated with an increase in serum
Cholesterol management
Recently, the NCEP published revised recommendations for cholesterol management in adults in the Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III, or ATP III).13, 14 The ATP III reasserted the importance of high levels of LDL-C as a risk factor for cardiovascular disease, and established low levels of HDL-C and elevated triglyceride levels as independent risk factors. Table 2 summarizes the new
Conclusions
Estrogen has an important role in the maintenance of cardiovascular health in women, and the loss of estrogen associated with menopause can increase the risk of cardiovascular disease. The cardioprotective effects of estrogen are mediated by ER-α and ER-β, and are both direct and indirect, with the direct effects being both rapid (rapid vasodilation) and longer-term (involving changes in the genetic expression of proteins that regulate vascular tone and the response to injury). To what degree
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Supported by a grant from Ortho-McNeil Pharmaceutical, Inc.