Abstract
Vascular endothelium expresses both the estrogen receptors (ERs) α and β, and ERα mediates development of early atherosclerosis in male mice. This process is thought to be testosterone-dependent. We hypothesized that male murine aortic endothelium produces robust levels of estradiol by aromatase conversion of testosterone, and that regulation of this process is mediated by the presence of ERs, primarily ERα. Aortic endothelium was isolated from ERα knockout (ERα -/-) and wild-type (ERα +/+) male mice and treated with testosterone or the 5α reduction product dihydrotestosterone (DHT), with or without the P450 aromatase inhibitor anastrazole, or a non-specific estrogen receptor antagonist. Aromatase gene expression and estradiol production were assayed. Treatment with testosterone, but not DHT, caused increased aromatase expression and estradiol production in ERα +/+ endothelium that was attenuated by disruption of ERα in the ERα -/- group. Anastrazole inhibition of aromatase reduced testosterone-induced aromatase expression and estradiol levels in both ERα -/- and ERα +/+ endothelium. Antagonism of both ERs decreased testosterone-induced aromatase expression in both wild-type and knockout groups. The effects of the receptor antagonist on estradiol production differed between the two groups, however, with a reduction in estradiol release from the ERα +/+ cells and complete abolition of estradiol release from the ERα -/- cells. Thus, estradiol production in vascular endothelium from male mice is robust, depends on the aromatic conversion of testosterone and requires functional ERα to achieve maximal levels of estradiol generation. Local vascular production of aromatase-mediated estradiol in response to circulating testosterone may affect ERα-dependent mechanisms to increase susceptibility to early atheroma formation in male mice. This pathway may have important therapeutic relevance for reducing the risk of atherosclerotic cardiovascular disease in human males.Electronic supplementary materialThe online version of this article (doi:10.1186/2193-1801-2-214) contains supplementary material, which is available to authorized users.
Highlights
Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of mortality for both men and women in Western societies
Disruption of the ERα accomplished by use of the ERα −/− mouse resulted in attenuation of the increase in levels of P450 aromatase seen in response to testosterone treatment (Figure 1B)
P450 aromatase still increased in a dose-dependent manner in the ERα −/− cells, this increase was reduced by two- to three-fold at each dose of testosterone compared to the cells isolated from ERα +/+ male
Summary
Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of mortality for both men and women in Western societies. Disparity exists between the incidence of cardiovascular disease in men and women of similar age, as well as between menopausal and premenopausal women (Kannel et al 1976). The mechanisms behind these discrepancies are yet poorly understood, the observations suggest the gender disparities in development of ASCVD stem in part from genderrelated differences in sex hormones, primarily estrogen and testosterone. Much emphasis has been placed on the atheroprotective effects of estrogens in females. This notion of atheroprotective estrogen has been assumed to include males, but accumulating evidence indicates that this simple paradigm does not accurately reflect the complexity of hormonal regulation of vascular disease. Sex hormones exert gender-specific effects, derived from both variations in the levels of sex hormones and from gender-related patterns of hormone and receptor tissue distribution leading to gender-specific responses (Vitale et al 2009; Villablanca et al 2004; Villablanca et al 2009)
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