Abstract
In modern society, cardiovascular disease remains the biggest single threat to life, being responsible for approximately one third of worldwide deaths. Male prevalence is significantly higher than that of women until after menopause, when the prevalence of CVD increases in females until it eventually exceeds that of men. Because of the coincidence of CVD prevalence increasing after menopause, the role of estrogen in the cardiovascular system has been intensively researched during the past two decades in vitro, in vivo and in observational studies. Most of these studies suggested that endogenous estrogen confers cardiovascular protective and anti-inflammatory effects. However, clinical studies of the cardioprotective effects of hormone replacement therapies (HRT) not only failed to produce proof of protective effects, but also revealed the potential harm estrogen could cause. The “critical window of hormone therapy” hypothesis affirms that the moment of its administration is essential for positive treatment outcomes, pre-menopause (3–5 years before menopause) and immediately post menopause being thought to be the most appropriate time for intervention. Since many of the cardioprotective effects of estrogen signaling are mediated by effects on the vasculature, this review aims to discuss the effects of estrogen on vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) with a focus on the role of estrogen receptors (ERα, ERβ and GPER) in triggering the more recently discovered rapid, or membrane delimited (non-genomic), signaling cascades that are vital for regulating vascular tone, preventing hypertension and other cardiovascular diseases.
Highlights
Estrogens are a class of steroid hormones that are mainly synthesized by the ovaries, adrenals and by the placenta in pregnancy
This study didn’t directly test whether the G-1-induced relaxation was Gα or cAMP-dependent, previous work from the same group reported that GPER-dependent coronary artery relaxation was due to cAMP/PKA-dependent phosphorylation and activation of myosin light chain phosphatase (MLCP) in vascular smooth muscle cells (VSMCs), which was in itself Gαs-dependent rather than Gαi (Yu et al, 2014)
Experimental studies demonstrated that endogenous E2 has vascular protective effects, the best described being that of mediating arterial vasodilation, preventing hypertension and the progression of atherosclerosis
Summary
Estrogens are a class of steroid hormones that are mainly synthesized by the ovaries, adrenals and by the placenta in pregnancy. Extragonadal E2 acts as a paracrine or autocrine modulator in its origin tissue, so for instance, would have a paracrine action in the vasculature (Simpson, 2003) Besides their role in developing the primary and secondary sexual characteristics of women, multiple studies have shown that they can protect the cardiovascular system of pre-menopausal women and men against disease (see (Novella et al, 2019; Iorga et al, 2017)). E2 is thought to be able to mitigate against hypertension (see (Ashraf and Vongpatanasin, 2006; Rafikova and Sullivan, 2014) It is a complicated picture because contrary to this is the possibility that long-term exposure to estrogen in the form of oral contraceptive or HRT medications may increase hypertension, due to the buildup of superoxide radicals (Subramanian et al, 2011; MohanKumar et al, 2011). The “theory of timing and opportunity” explained that whether estrogen administration is beneficial or deleterious, depends greatly on the stage of menopause (Menazza and Murphy, 2016; Dehaini et al, 2018)
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