Estrogen Receptors and Endothelium

Abstract

Estrogens, and in particular 17beta-estradiol (E2), play a pivotal role in sexual development and reproduction and are also implicated in a large number of physiological processes, including the cardiovascular system. Both acetylcholine-induced and flow-dependent vasodilation are preserved or potentiated by estrogen treatment in both animal models and humans. Indeed, E2 increases the endothelial production of nitric oxide and prostacyclin and prevents early atheroma through endothelial-mediated mechanisms. Furthermore, whereas it prevents endothelial activation, E2 potentiates the ability of several subpopulations of the circulating or resident immune cells to produce proinflammatory cytokines. The balance between these 2 actions could determine the final effect in a given pathophysiological process. E2 also promotes endothelial healing, as well as angiogenesis. Estrogen actions are essentially mediated by 2 molecular targets: estrogen receptor-alpha (ERalpha) and ERbeta. The analysis of mouse models targeted for ERalpha or ERbeta demonstrated a prominent role of ERalpha in vascular biology. ERalpha directly modulates transcription of target genes through 2 activation functions (AFs), AF-1 and AF-2. Interestingly, an AF-1-deficient ERalpha isoform can be physiologically expressed in the endothelium and appears sufficient to mediate most of the vasculoprotective actions of E2. In contrast, AF-1 is necessary for the E2 actions in reproductive targets. Thus, it appears conceivable to uncouple the vasculoprotective and sexual actions with appropriate selective ER modulators.

Predominant Role of Nuclear Versus Membrane Estrogen Receptor α in Arterial Protection: Implications for Estrogen Receptor α Modulation in Cardiovascular Prevention/Safety

“…Because NO is a well‐recognized vasculoprotective mediator and guardian of arterial integrity,27 and because 17β‐estradiol stimulates endothelial NO production through ERα MISS activation,22 one of the main surprises and unexpected findings in the present study is the absence of a role of ERα MISS on vascular protection. Indeed, it is largely believed that the increase in endothelium‐derived NO plays an important role in the vasculoprotective actions of estrogens, in particular in their atheroprotective action 18, 64. Interestingly, present finding is strikingly consistent with our previous work published 20 years ago, reporting that the atheroprotective effect of exogenous 17β‐estradiol was not altered by NOS inhibition 65.…”

“…ERβ plays a key role in cardiac protection,17 and ERα, especially in the endothelium, is involved in the beneficial vascular actions of 17β‐estradiol 18. Indeed, most of the vascular actions of 17β‐estradiol are abrogated in mice lacking ERα in both endothelial and hematopoietic cells by breeding Tie2‐Cre transgenic mice (expressing the Cre recombinase under the control of the endothelial tyrosine‐protein kinase receptor (Tie2) promoter) with ERα‐floxed mice at exon 2 (ERα lox/lox ) 8, 15, 19.…”

“…Indeed, most of the vascular actions of 17β‐estradiol are abrogated in mice lacking ERα in both endothelial and hematopoietic cells by breeding Tie2‐Cre transgenic mice (expressing the Cre recombinase under the control of the endothelial tyrosine‐protein kinase receptor (Tie2) promoter) with ERα‐floxed mice at exon 2 (ERα lox/lox ) 8, 15, 19. Thus, the endothelium, a guardian of arterial integrity, represents a promising cellular target for 17β‐estradiol via the activation of ERα 18. Beside the well‐recognized role of nuclear ERα, which regulates target gene transcription (genomic action) through activation functions (AFs) 1 and 2,16, 20 a subpopulation of ERα is present at or near the plasma membrane, where it can elicit rapid, nongenomic, membrane‐initiated steroid signaling (MISS) effects 21, 22, 23, 24, 25…”

The Effect of Cardiovascular Responses after Aerobic Exercise in Menstrual Cycle

“…Decreased estrogen levels during menstruation influence an increase of peripheral resistance as the sympathetic nervous system is more activated and peripheral blood vessels are more contracted [1]. At ovulation, increased estrogen levels not only affect vascular relaxation by triggering the activation of nitric oxide, the vascular relaxant factor, but also are attributable to a lower blood pressure during exercise than at menstruation by having a direct relaxant effect on the smooth muscles [19]. Until now, multiple studies have de- Blood pressure is affected by CO = HR × SV and TPR.…”

“…In addition, norepinephrine levels, an indicator of sympathetic activity, are higher in the menstruation phase than in the ovulation phase [20]. Whereas, the increased levels of estrogen in the ovulation phase induce vascular relaxation by directly stimulating vascular endothelial cells and also decrease BP during exercise through relaxation of peripheral blood vessels by promoting activation of nitric oxide which is a vascular relaxant factor [8] [19].…”