Estrogen Receptor and Vascular Aging

Abstract

Cardiovascular diseases remain an age-related pathology in both men and women. These pathologies are 3-fold more frequent in men than in women before menopause, although this difference progressively decreases after menopause. The vasculoprotective role of estrogens are well established before menopause, but the consequences of their abrupt decline on the cardiovascular risk at menopause remain debated. In this review, we will attempt to summarize the main clinical and experimental studies reporting the protective effects of estrogens against cardiovascular diseases, with a particular focus on atherosclerosis, and the impact of aging and estrogen deprivation on their endothelial actions. The arterial actions of estrogens, but also part of that of androgens through their aromatization into estrogens, are mediated by the estrogen receptor (ER)α and ERβ. ERs belong to the nuclear receptor family and act by transcriptional regulation in the nucleus, but also exert non-genomic/extranuclear actions. Beside the decline of estrogens at menopause, abnormalities in the expression and/or function of ERs in the tissues, and particularly in arteries, could contribute to the failure of classic estrogens to protect arteries during aging. Finally, we will discuss how recent insights in the mechanisms of action of ERα could contribute to optimize the hormonal treatment of the menopause.

Keywords: atherosclerosis; endothelium; estradiol; estrogen receptor; menopause; vascular aging.

FIGURE 1

Evolution of sex hormones levels and incidence of coronary heart diseases in men and women through life. During their life, women are at lower risk to develop coronary heart diseases (CHD) compared to men. In both sexes, aging is associated to an increased incidence of CHD. In addition, while testosterone levels decrease progressively with aging in men, estradiol levels rapidly drop at the onset of menopause in women and is associated to a rise in CHD (adapted from Lerner and Kannel (1986)). A.U, Arbitrary unit.

FIGURE 2

Factors involved in the loss of E2 vascular protection after menopause. Both duration of estrogen deprivation and aging per se could contribute to the loss of E2-mediated vascular protection in postmenopausal women, in part by altering ERα expression and/or function.

FIGURE 3

Respective role of ERαMISS and nuclear ERα in E2-mediated vascular protection in endothelial cells. Fixation of 17β-estradiol (E2) triggers conformational changes in ERα structure, leading to the recruitment of co-activators. Co-activators facilitate ERα binding to DNA and the recruitment of RNA polymerase (RNA pol III) which initiates transcription. In addition, ERα can localise to the plasma membrane after palmitoylation and mediates rapid membrane-initiated steroid signaling (ERαMISS) by interacting with different signaling pathway such as G protein, SRC, PI3K and eNOS. NO production and acceleration of endothelial healing in response to E2 depend on ERαMISS, while flow-mediated outward remodeling and prevention of atherosclerosis depend on nuclear ERα. Adapted from Guivarc’h et al. (2018), Adlanmerini et al. (2020), Zahreddine et al. (2020).

FIGURE 4

Testosterone-mediated vascular protection is mediated by both AR and ERα in males. In males, testosterone is the predominant sex hormone. Testosterone can be converted into dihydrotestosterone by the 5α-reductase and bind to the Androgen Receptor (AR). In addition, testosterone can also be converted into 17β-estradiol by the aromatase and act on ERα. Both AR and ERα mediate vascular protective effects in males, including endothelial-dependent dilation, protection against atherosclerosis, and flow-mediated remodeling.