Estrogen receptor β actions in the female cardiovascular system: A systematic review of animal and human studies

Muka, Taulant; Vargas, Kris G.; Jaspers, Loes; Wen, Kexin; Dhana, Klodian; Vitezova, Anna; Nano, Jana; Brahimaj, Adela; Colpani, Verônica; Kraja, Bledar; Začiragić, Asija; Bramer, Wichor M.; Dijk, Gaby M.van; Kavousi, Maryam; Franco, Oscar H.

doi:10.1016/j.maturitas.2016.01.009

Cited by 32 publications

(19 citation statements)

References 119 publications

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“…Our observations that measures of CEF (CSA and CBF) are better in younger women, compared to older women and CBF is better in younger women compared to age matched men are consistent with prior epidemiological observational studies showing that premenopausal women are protected from cardiovascular events compared to men of similar ages but that after menopause the sex disparities in CVD morbidity and mortality diminishes [ 3 ]. CVD remains the leading cause of mortality in women particularly after menopause, and this is hypothesized to be due to the loss of the protective effect of estrogen [ 47 , 48 ]. A recent study showed that women who experience premature menopause have a higher risk of CVD mortality than do women who experience menopause later in life; therefore, the higher CV risk in women is less likely an aging effect alone [ 6 ].…”

Section: Discussionmentioning

confidence: 99%

Coronary endothelial function is better in healthy premenopausal women than in healthy older postmenopausal women and men

et al. 2017

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BackgroundPremenopausal women have fewer cardiovascular disease (CVD) events than postmenopausal women and age-matched men, but the reasons are not fully understood. Coronary endothelial function (CEF), a barometer of coronary vascular health, promises important insights into age and sex differences in atherosclerotic CVD risk, but has not been well characterized in healthy individuals because of the invasive nature of conventional CEF measurements. Recently developed magnetic resonance imaging (MRI) methods were used to quantify CEF (coronary area and flow changes in response to isometric handgrip exercise (IHE), an endothelial-dependent stressor) to test the hypothesis that healthy women have better CEF compared to men particularly at a younger age.MethodsThe study participants were 50 healthy women and men with no history of coronary artery disease (CAD) or traditional CV risk factors and Agatston coronary calcium score (on prior CT) <10 for those ≥ 50 years. Coronary cross-sectional area (CSA) measurements and flow-velocity encoded images (CBF) were obtained at baseline and during continuous IHE using 3T breath-hold cine MRI-IHE. CEF (%change in CSA and CBF with IHE) comparisons were made according to age and sex, and all women ≥50 years were post-menopausal.ResultsIn the overall population, there were no differences in CEF between men and women. However, when stratified by age and sex the mean changes in CSA and CBF during IHE were higher in younger premenopausal women than older postmenopausal women (%CSA: 15.2±10.6% vs. 7.0±6.8%, p = 0.03 and %CBF: 59.0±37.0% vs. 30.5±24.5% p = 0.02). CBF change was also nearly two-fold better in premenopausal women than age-matched men (59.0±37.0% vs. 33.6±12.3%, p = 0.03).ConclusionsPremenopausal women have nearly two-fold better mean CEF compared to postmenopausal women. CEF, measured by CBF change is also better in premenopausal women than age-matched men but there are no sex differences in CEF after menopause. Fundamental age and sex differences in CEF exist and may contribute to differences in the development and clinical manifestations of atherosclerotic CVD, and guide future trials targeting sex-specific mechanisms of atherogenesis.

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Section: Discussionmentioning

confidence: 99%

Coronary endothelial function is better in healthy premenopausal women than in healthy older postmenopausal women and men

et al. 2017

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“…Numerous studies prove that the cardioprotective effects of estrogens are mediated by the nitric oxide- (NO-) dependent pathway [7]. Similarly to NO, carbon monoxide (CO) also plays an important role in the estrogen-mediated cardioprotection.…”

Section: Introductionmentioning

confidence: 99%

Cardioprotective Effect of Selective Estrogen Receptor Modulator Raloxifene Are Mediated by Heme Oxygenase in Estrogen-Deficient Rat

Pósa

Szabó

Kupai

et al. 2017

Oxidative Medicine and Cellular Longevity

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Estrogens and raloxifene (RAL) have beneficial effects on certain cardiovascular indices in postmenopausal women characterized by estrogen deficiency. Heme oxygenase (HO) activity is increased by 17β-estradiol (E2) and RAL in estrogen-deficient rat resulting in vasorelaxation mediated by carbon monoxide. We determined the expressions of HO in cardiac and aortic tissues after ovariectomy (OVX) and subsequent RAL or E2 treatment. We investigated the effects of pharmacological inhibition of HO enzyme on the arginine vasopressin- (AVP-) induced blood pressure in vivo, the epinephrine- and phentolamine-induced electrocardiogram ST segment changes in vivo, and the myeloperoxidase (MPO) enzyme activity. When compared with intact females, OVX decreased the HO-1 and HO-2 expression, aggravated the electrocardiogram signs of heart ischemia and the blood pressure response to AVP, and increased the cardiac MPO. E2 and RAL are largely protected against these negative impacts induced by OVX. The pharmacological inhibition of HO in E2- or RAL-treated OVX animals, however, restored the cardiovascular status close to that observed in nontreated OVX animals. The decreased expression of HO enzymes and the changes in blood pressure ischemia susceptibility and inflammatory state in OVX rat can be reverted by the administration of E2 or RAL partly through its antioxidant and anti-inflammatory roles.

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“…Most studies document expression of these receptors, rather than relative expression. ER-β is also known to be involved in multiple aspects of SMC function and development, such as contraction, maturation, proliferation, and migration [58, 59]. It is possible that the effects observed in this study are the result of differential expression of ERs.…”

Section: Discussionmentioning

confidence: 92%

Cell sex affects extracellular matrix protein expression and proliferation of smooth muscle progenitor cells derived from human pluripotent stem cells

Wen

Green

et al. 2017

Stem Cell Res Ther

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BackgroundSmooth muscle progenitor cells (pSMCs) differentiated from human pluripotent stem cells (hPSCs) hold great promise for treating diseases or degenerative conditions involving smooth muscle pathologies. However, the therapeutic potential of pSMCs derived from men and women may be very different. Cell sex can exert a profound impact on the differentiation process of stem cells into somatic cells. In spite of advances in translation of stem cell technologies, the role of cell sex and the effect of sex hormones on the differentiation towards mesenchymal lineage pSMCs remain largely unexplored.MethodsUsing a standard differentiation protocol, two human embryonic stem cell lines (one male line and one female line) and three induced pluripotent stem cell lines (one male line and two female lines) were differentiated into pSMCs. We examined differences in the differentiation of male and female hPSCs into pSMCs, and investigated the effect of 17β-estradiol (E2) on the extracellular matrix (ECM) metabolisms and cell proliferation rates of the pSMCs. Statistical analyses were performed by using Student’s t test or two-way ANOVA, p < 0.05.ResultsMale and female hPSCs had similar differentiation efficiencies and generated morphologically comparable pSMCs under a standard differentiation protocol, but the derived pSMCs showed sex differences in expression of ECM proteins, such as MMP-2 and TIMP-1, and cell proliferation rates. E2 treatment induced the expression of myogenic gene markers and suppressed ECM degradation activities through reduction of MMP activity and increased expression of TIMP-1 in female pSMCs, but not in male pSMCs.ConclusionshPSC-derived pSMCs from different sexes show differential expression of ECM proteins and proliferation rates. Estrogen appears to promote maturation and ECM protein expression in female pSMCs, but not in male pSMCs. These data suggest that intrinsic cell-sex differences may influence progenitor cell biology.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-017-0606-2) contains supplementary material, which is available to authorized users.

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Estrogen receptor β actions in the female cardiovascular system: A systematic review of animal and human studies

Cited by 32 publications

References 119 publications

Coronary endothelial function is better in healthy premenopausal women than in healthy older postmenopausal women and men

Coronary endothelial function is better in healthy premenopausal women than in healthy older postmenopausal women and men

Cardioprotective Effect of Selective Estrogen Receptor Modulator Raloxifene Are Mediated by Heme Oxygenase in Estrogen-Deficient Rat

Cell sex affects extracellular matrix protein expression and proliferation of smooth muscle progenitor cells derived from human pluripotent stem cells

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