The Journal of Steroid Biochemistry and Molecular Biology
Mechanisms of estrogen action in the cardiovascular system
Section snippets
Vascular estrogen receptors
Two estrogen receptors are currently known; ERα and ERβ, and their molecular biology and mechanism of action are reviewed in detail elsewhere in this issue. Normal blood vessels are complex structures, with walls comprised principally of smooth muscles cells and an endothelial cell lining (Fig. 1). Vascular endothelial cells and smooth muscle cells first were found to bind estrogen with high affinity two decades ago [6]. Estrogen receptors α and β recently have been identified in vascular
Vascular cell exposure to estrogens
Vascular cells are exposed to estrogens from a number of sources. In premenopausal women, 17β-estradiol produced by the ovaries is the major circulating estrogenic compound, though a large number of other circulating estrogens and estrogen metabolites have been identified. Circulating estradiol concentrations, low in adolescent girls, begin to cycle in women with the onset of menses, ranging from less than 0.36 nM in the follicular phase to about 2.8 nM in midcycle. During pregnancy,
Rapid, non-genomic effects of estrogen
In normal blood vessels, the endothelium releases nitric oxide in response to a variety of stimuli, leading to vasodilation [31]. In diseased blood vessels with dysfunctional endothelium, release of nitric oxide is attenuated, leading to direct stimulation of smooth muscle contraction and ‘paradoxical’ vasoconstriction in response to the same stimuli [31]. Estrogen acutely enhances vasorelaxation via both endothelium-independent and endothelium-dependent pathways. These effects are non-genomic
Estrogen receptors and vascular injury
Estrogen increases levels of gene expression for many genes in the cardiovascular system (reviewed in [1]), such as the important vasodilator-producing enzymes, prostacyclin synthase and nitric oxide synthase [52], [53]. Thus, eNOS is both rapidly activated by estrogen and the eNOS gene expression is also up-regulated by estrogen. Teleologically, this underscores the potential importance of the eNOS-NO system in estrogen's vascular effects (and vascular biology in general). Genes for both the
Estrogen receptors in the myocardium: preliminary studies in ERβ knockout mice
Myocardial cells also express ERα and ERβ [1]. In preliminary studies, we have examined the effects of ERβ disruption on myocardial function in 10–12-month-old male mice. A total of 20 mice were studied, five male and five female ERβ knockout mice, and five littermate controls of each sex. These are very small numbers and the data are thus quite preliminary, but the male ERβ knockout mice displayed an interesting myocardial phenotype: their hearts were smaller (Fig. 2) and ‘hypercontractile’
Summary
Estrogen, thus, has both rapid and longer-term effects on the blood vessel wall. Data regarding the mechanism(s) that mediate the rapid effects of estrogen on vasodilation support that liganded estrogen receptor increases the bioavailability of endothelial-derived nitric oxide in a non-genomic fashion, which, through NO-mediated increases in cyclic GMP, leads to vascular smooth muscle cell relaxation. The longer-term effects of estrogen, likely are due to ERα and/or ERβ-mediated changes in
Acknowledgements
Supported in part by NIH Grants HL55309, HL56069, and HL59953 to MEM. MEM is an Established Investigator of the American Heart Association. The author gratefully acknowledges Richard Karas and Rick Patten as well as the other investigators of the Molecular Cardiology Research Center, who have made the work described here possible.
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