Comprehensive Physiology Wiley Online Library

Mechanisms of Sex Disparities in Cardiovascular Function and Remodeling

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ABSTRACT

Epidemiological studies demonstrate disparities between men and women in cardiovascular disease prevalence, clinical symptoms, treatments, and outcomes. Enrollment of women in clinical trials is lower than men, and experimental studies investigating molecular mechanisms and efficacy of certain therapeutics in cardiovascular disease have been primarily conducted in male animals. These practices bias data interpretation and limit the implication of research findings in female clinical populations. This review will focus on the biological origins of sex differences in cardiovascular physiology, health, and disease, with an emphasis on the sex hormones, estrogen and testosterone. First, we will briefly discuss epidemiological evidence of sex disparities in cardiovascular disease prevalence and clinical manifestation. Second, we will describe studies suggesting sexual dimorphism in normal cardiovascular function from fetal life to older age. Third, we will summarize and critically discuss the current literature regarding the molecular mechanisms underlying the effects of estrogens and androgens on cardiac and vascular physiology and the contribution of these hormones to sex differences in cardiovascular disease. Fourth, we will present cardiovascular disease risk factors that are positively associated with the female sex, and thus, contributing to increased cardiovascular risk in women. We conclude that inclusion of both men and women in the investigation of the role of estrogens and androgens in cardiovascular physiology will advance our understanding of the mechanisms underlying sex differences in cardiovascular disease. In addition, investigating the role of sex‐specific factors in the development of cardiovascular disease will reduce sex and gender disparities in the treatment and diagnosis of cardiovascular disease. © 2019 American Physiological Society. Compr Physiol 9:375‐411, 2019.

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Figure 1. Figure 1. Proportion of women that were enrolled in randomized controlled trials (RCT) compared with (A) proportion of women in the general population with a given disease and (B) proportion of women that died from each disease (). In this study, the authors reviewed all RCTs that used to construct the American Heart Association guidelines for cardiovascular disease in women (). The proportion of women enrolled in randomized controlled trials is lower compared with their representation in the disease populations being treated. The major diseases presented in this figure include coronary artery disease, heart failure, diabetes, hypercholesteremia, and hypertension. Whiskers represent the upper 95th percentile of the confidence interval for the proportion of women in RCTs. Hypercholesteremia is defined as low‐density lipoprotein cholesterol >130 mg/dL. Reprinted with permission ().
Figure 2. Figure 2. Longitudinal trajectories of systolic and diastolic blood pressures (BP) from childhood to adulthood by race‐sex groups. Curve parameters that were compared statistically: β0 = the intercept (the level of BP) at age point of 20.1 years; β1 = overall linear slopes (the tangent line) at age point of 20.1 years; β2 = nonlinear slopes in young adulthood during 20 to 35 years; β3 = nonlinear slopes in middle‐aged adulthood during 36 to 51 years. All curve parameters (β0, β1, β2, and β3) were significantly different from 0 (P < 0.001) except β2 = − 0.05 (P = 0.023) and β3 = 0.0001 (P = 0.965) for diastolic BP in black men. Reprinted with permission ().
Figure 3. Figure 3. Changes in left ventricular parameters with age in healthy males (left) and females (right). A total of 96 subjects were recruited in this study (76 adults aged 21‐81 years and 20 children aged 11‐15 years, all Caucasian). Solid lines represent rational polynomial curve fit and dashed lines the 95% prediction intervals of this fit. LVM = left ventricular mass, BSA = body surface area, EDV = end‐diastolic volume. Reprinted from (), an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0).
Figure 4. Figure 4. Changes in the total (A) and bioavailable (B) estrogen with age in men (solid lines, squares) and women (dashed lines, circles). Subjects were recruited from an age‐stratified random sample of Rochester, MN, using the medical records linkage system of the Rochester Epidemiology Project. Estrogen was measured by RIA in fasting serum samples collected between 0800 and 0900 h. There was a reduction in serum total and bioavailable estrogen concentrations around the time of menopause and an age‐related reduction in bioavailable concentrations of estrogen in men. Reprinted with permission ().
Figure 5. Figure 5. Nongenomic estrogen receptor signaling in vascular endothelial (A) and smooth muscle cells (B). ERs are localized to caveolae in the cell membrane of endothelial and vascular smooth muscles cells by interacting with caveolin‐1 and scaffold protein striatin. (A) In vascular endothelial cells, binding of estrogen to ERs causes ER‐G protein complex formation with subsequent activation of tyrosine kinase Src, serine/threonine kinase PI3K, Akt, and MAPK. Kinases induce phosphorylation of eNOS (at serine 1177). Activation of eNOS leads to production of NO that contributes to vasodilatation, proliferation, and migration of endothelial cells. (B) In vascular smooth muscle cells, activation of ERs by estrogen induces activation of phosphatases and inhibition of kinases. These events result in cell proliferation and migration. Akt: protein kinase B; eNOS: endothelial nitric oxide synthase; ER: estrogen receptor; MAPK: mitogen‐activated protein kinase; NO: nitric oxide; PI3K: phosphatidylinositol‐3‐OH kinase. Reprinted with permission ().
Figure 6. Figure 6. Mechanisms of coronary artery relaxation mediated by estrogen via GPR‐30. (A) Endothelium‐independent mechanism: Binding of estrogen to GPR‐30 leads to activation of BK channels, causing potassium efflux, hyperpolarization, and relaxation of the coronary smooth muscle cells. (B) Endothelium‐dependent mechanism: GPR‐30 activation leads to NO synthesis and vascular relaxation. BK: large conductance calcium‐activated potassium channel; GPR‐30: G‐protein‐coupled receptor; NO: nitric oxide. Reprinted with permission ().
Figure 7. Figure 7. ER β mRNA expression in the hearts of patients with aortic stenosis (AS) in total population (A) and comparisons between men and women (B) in control and patient samples. (A) ER‐β mRNA content was significantly increased in AS patients (P < 0.0001). (B) ER‐β mRNA content was significantly higher in hearts from healthy men compared with healthy women (P < 0.005) and in men and women with AS, as compared to their respective controls (P < 0.05, P < 0.001, respectively). The percent increase in ER‐β mRNA was more pronounced in female than in male patients (P < 0.005, not shown in the figure). Reprinted with permission ().
Figure 8. Figure 8. Gene ontology (GO) analysis for identification of genes that are different between sexes. GO analysis was performed using Metacore. The gene set identified at predetermined number of false discovery rate was used to probe the cellular localization of genes, the processes in which they are involved, the metabolic networks, and their potential pathways. The P values on the graph (x‐axis) indicate the probability of mapping of an experiment to a process to arise by chance. Reprinted with permission ().
Figure 9. Figure 9. Estradiol or an estrogen‐dendrimer conjugate (EDC) improves functional recovery and infarct size in ovariectomized mice after ischemia/reperfusion (I/R) injury. (A) I/R protocol in bilaterally ovariectomized C57BL/6 J mice with subcutaneous Alzet mini‐pumps implantation for drug treatments for two weeks. Two‐week treatment with estradiol or EDC improved functional cardiac parameters. (B, E) left ventricular diastolic pressure (LVDP), (C, F) rate pressure product (RPP), (D, G) infarct size. To assess postischemic recovery of parameters LVDP and RPP, values were expressed as percentage of their preischemic values. Infarct size was expressed as percentage of total area of cross‐sectional slices. (n = 6 for each group). Values are mean ± SEM. **P < 0.01. Reprinted with permission ().
Figure 10. Figure 10. Changes in the diameter of coronary arteries from female (left) and male (right) patients in response to intracoronary infusion of acetylcholine (1.6 μmol/min, open bars; 16 μmol/min, stippled bars) before and after 2.5 μmol intracoronary infusion of 17β‐estradiol. In females, net constriction before estrogen was converted to dilatation after estrogen (* indicates P < 0.01 before vs. after estrogen). The study population included nine postmenopausal women (59 ± 3 years old) and seven men (52 ± 4 years old) with coronary artery disease. Values are mean ± SEM. Reprinted with permission ().
Figure 11. Figure 11. Changes in the total (A) and bioavailable (B) testosterone with age in men (solid lines, squares) and women (dashed lines, circles). Subjects were recruited from an age‐stratified random sample of Rochester, MN, using the medical records linkage system of the Rochester Epidemiology Project. Testosterone was measured by RIA in fasting serum samples collected between 0800 and 0900 h. There was a decline in serum total and bioavailable testosterone concentrations in both men and women but the drop in bioavailable testosterone was twice that in total testosterone. Bioavailable testosterone was reduced by 64% and 28% in the men and women, respectively. Reprinted with permission ().
Figure 12. Figure 12. Cumulative concentration‐response curves to (A) progesterone (Prog, 10 nmol/L‐300 μmol/L) and (B) estradiol (E2, 10 nmol/L‐30 μmol/L) in the presence or absence propargylglycine (PAG), an inhibitor of H2S‐synthesizing enzyme cystathionine‐γ lyase (CSE). H2S production was determined in aortic tissues incubated with (C) Prog (100 μmol/L) and (D) E2 (10 μmol/L) for 15 or 30 min and (C and D) testosterone (T, 10 umol/L) for 30 min in presence of L‐cysteine (L‐Cys). ###P < 0.001 versus basal; °°°P < 0.001 versus L‐Cys; n = 6. Values are mean ± SEM. Reprinted with permission ().
Figure 13. Figure 13. Time from pregnancy to time of onset of cardiovascular disease (comprised ischemic heart disease, stroke, and heart disease) in women who had experienced a hypertensive disorder of pregnancy (HDP) or a normal pregnancy. The cardiovascular disease composite outcome was greater in women with HDP as compared with women who remained normotensive during pregnancy. Reprinted with permission ().
Figure 14. Figure 14. Circulating concentrations of testosterone (A), estradiol (B), testosterone‐to‐estradiol ratio (C), and placental aromatase and 17[beta]‐HSD3 (17[beta]‐hydroxysteroid dehydrogenase 3) expression (D and E) in women diagnosed with early‐onset preeclampsia (E‐PE) and normotensive pregnant women matched for gestational age (26‐34 weeks). E‐PE patients had higher concentrations of testosterone, lower concentration of estradiol, higher testosterone to estradiol ratio and greater protein expression of placental aromatase and 17[beta]‐HSD3. Values are mean ± SEM (A‐C) or mean ± SD (E). *P < 0.05; **P < 0.01. Reprinted with permission ().
Figure 15. Figure 15. Dose‐response analysis of parity number. Nine prospective studies were included in this meta‐analysis. The summary risk estimates for per live birth was 1.01 (95% CI, 0.97‐1.05), with significant heterogeneity (I2  =  86.4%; P < 0.001). Nonlinear dose‐response analysis revealed a J‐shaped relationship between parity number and mortality from cardiovascular disease. Reprinted from (), an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0).


Figure 1. Proportion of women that were enrolled in randomized controlled trials (RCT) compared with (A) proportion of women in the general population with a given disease and (B) proportion of women that died from each disease (). In this study, the authors reviewed all RCTs that used to construct the American Heart Association guidelines for cardiovascular disease in women (). The proportion of women enrolled in randomized controlled trials is lower compared with their representation in the disease populations being treated. The major diseases presented in this figure include coronary artery disease, heart failure, diabetes, hypercholesteremia, and hypertension. Whiskers represent the upper 95th percentile of the confidence interval for the proportion of women in RCTs. Hypercholesteremia is defined as low‐density lipoprotein cholesterol >130 mg/dL. Reprinted with permission ().


Figure 2. Longitudinal trajectories of systolic and diastolic blood pressures (BP) from childhood to adulthood by race‐sex groups. Curve parameters that were compared statistically: β0 = the intercept (the level of BP) at age point of 20.1 years; β1 = overall linear slopes (the tangent line) at age point of 20.1 years; β2 = nonlinear slopes in young adulthood during 20 to 35 years; β3 = nonlinear slopes in middle‐aged adulthood during 36 to 51 years. All curve parameters (β0, β1, β2, and β3) were significantly different from 0 (P < 0.001) except β2 = − 0.05 (P = 0.023) and β3 = 0.0001 (P = 0.965) for diastolic BP in black men. Reprinted with permission ().


Figure 3. Changes in left ventricular parameters with age in healthy males (left) and females (right). A total of 96 subjects were recruited in this study (76 adults aged 21‐81 years and 20 children aged 11‐15 years, all Caucasian). Solid lines represent rational polynomial curve fit and dashed lines the 95% prediction intervals of this fit. LVM = left ventricular mass, BSA = body surface area, EDV = end‐diastolic volume. Reprinted from (), an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0).


Figure 4. Changes in the total (A) and bioavailable (B) estrogen with age in men (solid lines, squares) and women (dashed lines, circles). Subjects were recruited from an age‐stratified random sample of Rochester, MN, using the medical records linkage system of the Rochester Epidemiology Project. Estrogen was measured by RIA in fasting serum samples collected between 0800 and 0900 h. There was a reduction in serum total and bioavailable estrogen concentrations around the time of menopause and an age‐related reduction in bioavailable concentrations of estrogen in men. Reprinted with permission ().


Figure 5. Nongenomic estrogen receptor signaling in vascular endothelial (A) and smooth muscle cells (B). ERs are localized to caveolae in the cell membrane of endothelial and vascular smooth muscles cells by interacting with caveolin‐1 and scaffold protein striatin. (A) In vascular endothelial cells, binding of estrogen to ERs causes ER‐G protein complex formation with subsequent activation of tyrosine kinase Src, serine/threonine kinase PI3K, Akt, and MAPK. Kinases induce phosphorylation of eNOS (at serine 1177). Activation of eNOS leads to production of NO that contributes to vasodilatation, proliferation, and migration of endothelial cells. (B) In vascular smooth muscle cells, activation of ERs by estrogen induces activation of phosphatases and inhibition of kinases. These events result in cell proliferation and migration. Akt: protein kinase B; eNOS: endothelial nitric oxide synthase; ER: estrogen receptor; MAPK: mitogen‐activated protein kinase; NO: nitric oxide; PI3K: phosphatidylinositol‐3‐OH kinase. Reprinted with permission ().


Figure 6. Mechanisms of coronary artery relaxation mediated by estrogen via GPR‐30. (A) Endothelium‐independent mechanism: Binding of estrogen to GPR‐30 leads to activation of BK channels, causing potassium efflux, hyperpolarization, and relaxation of the coronary smooth muscle cells. (B) Endothelium‐dependent mechanism: GPR‐30 activation leads to NO synthesis and vascular relaxation. BK: large conductance calcium‐activated potassium channel; GPR‐30: G‐protein‐coupled receptor; NO: nitric oxide. Reprinted with permission ().


Figure 7. ER β mRNA expression in the hearts of patients with aortic stenosis (AS) in total population (A) and comparisons between men and women (B) in control and patient samples. (A) ER‐β mRNA content was significantly increased in AS patients (P < 0.0001). (B) ER‐β mRNA content was significantly higher in hearts from healthy men compared with healthy women (P < 0.005) and in men and women with AS, as compared to their respective controls (P < 0.05, P < 0.001, respectively). The percent increase in ER‐β mRNA was more pronounced in female than in male patients (P < 0.005, not shown in the figure). Reprinted with permission ().


Figure 8. Gene ontology (GO) analysis for identification of genes that are different between sexes. GO analysis was performed using Metacore. The gene set identified at predetermined number of false discovery rate was used to probe the cellular localization of genes, the processes in which they are involved, the metabolic networks, and their potential pathways. The P values on the graph (x‐axis) indicate the probability of mapping of an experiment to a process to arise by chance. Reprinted with permission ().


Figure 9. Estradiol or an estrogen‐dendrimer conjugate (EDC) improves functional recovery and infarct size in ovariectomized mice after ischemia/reperfusion (I/R) injury. (A) I/R protocol in bilaterally ovariectomized C57BL/6 J mice with subcutaneous Alzet mini‐pumps implantation for drug treatments for two weeks. Two‐week treatment with estradiol or EDC improved functional cardiac parameters. (B, E) left ventricular diastolic pressure (LVDP), (C, F) rate pressure product (RPP), (D, G) infarct size. To assess postischemic recovery of parameters LVDP and RPP, values were expressed as percentage of their preischemic values. Infarct size was expressed as percentage of total area of cross‐sectional slices. (n = 6 for each group). Values are mean ± SEM. **P < 0.01. Reprinted with permission ().


Figure 10. Changes in the diameter of coronary arteries from female (left) and male (right) patients in response to intracoronary infusion of acetylcholine (1.6 μmol/min, open bars; 16 μmol/min, stippled bars) before and after 2.5 μmol intracoronary infusion of 17β‐estradiol. In females, net constriction before estrogen was converted to dilatation after estrogen (* indicates P < 0.01 before vs. after estrogen). The study population included nine postmenopausal women (59 ± 3 years old) and seven men (52 ± 4 years old) with coronary artery disease. Values are mean ± SEM. Reprinted with permission ().


Figure 11. Changes in the total (A) and bioavailable (B) testosterone with age in men (solid lines, squares) and women (dashed lines, circles). Subjects were recruited from an age‐stratified random sample of Rochester, MN, using the medical records linkage system of the Rochester Epidemiology Project. Testosterone was measured by RIA in fasting serum samples collected between 0800 and 0900 h. There was a decline in serum total and bioavailable testosterone concentrations in both men and women but the drop in bioavailable testosterone was twice that in total testosterone. Bioavailable testosterone was reduced by 64% and 28% in the men and women, respectively. Reprinted with permission ().


Figure 12. Cumulative concentration‐response curves to (A) progesterone (Prog, 10 nmol/L‐300 μmol/L) and (B) estradiol (E2, 10 nmol/L‐30 μmol/L) in the presence or absence propargylglycine (PAG), an inhibitor of H2S‐synthesizing enzyme cystathionine‐γ lyase (CSE). H2S production was determined in aortic tissues incubated with (C) Prog (100 μmol/L) and (D) E2 (10 μmol/L) for 15 or 30 min and (C and D) testosterone (T, 10 umol/L) for 30 min in presence of L‐cysteine (L‐Cys). ###P < 0.001 versus basal; °°°P < 0.001 versus L‐Cys; n = 6. Values are mean ± SEM. Reprinted with permission ().


Figure 13. Time from pregnancy to time of onset of cardiovascular disease (comprised ischemic heart disease, stroke, and heart disease) in women who had experienced a hypertensive disorder of pregnancy (HDP) or a normal pregnancy. The cardiovascular disease composite outcome was greater in women with HDP as compared with women who remained normotensive during pregnancy. Reprinted with permission ().


Figure 14. Circulating concentrations of testosterone (A), estradiol (B), testosterone‐to‐estradiol ratio (C), and placental aromatase and 17[beta]‐HSD3 (17[beta]‐hydroxysteroid dehydrogenase 3) expression (D and E) in women diagnosed with early‐onset preeclampsia (E‐PE) and normotensive pregnant women matched for gestational age (26‐34 weeks). E‐PE patients had higher concentrations of testosterone, lower concentration of estradiol, higher testosterone to estradiol ratio and greater protein expression of placental aromatase and 17[beta]‐HSD3. Values are mean ± SEM (A‐C) or mean ± SD (E). *P < 0.05; **P < 0.01. Reprinted with permission ().


Figure 15. Dose‐response analysis of parity number. Nine prospective studies were included in this meta‐analysis. The summary risk estimates for per live birth was 1.01 (95% CI, 0.97‐1.05), with significant heterogeneity (I2  =  86.4%; P < 0.001). Nonlinear dose‐response analysis revealed a J‐shaped relationship between parity number and mortality from cardiovascular disease. Reprinted from (), an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0).
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Teaching Material

S. Chaudhari, S. C. Cushen, O. Osikoya, P. A. Jaini, R. Posey, K. W. Mathis, S. Goulopoulou. Mechanisms of Sex Disparities in Cardiovascular Function and Remodeling. Compr Physiol 9: 2019, 405-441.

Didactic Synopsis

Major Teaching Points:

  1. Understanding the role of estrogens and androgens in normal vascular and cardiac physiology is necessary to explain their contribution to sex disparities in cardiovascular disease.
  2. Estrogen receptors are expressed on cardiomyocytes, vascular endothelial and smooth muscle cells and mediate the cardioprotective effects of estrogen in women via genomic and nongenomic pathways.
  3. Physiological concentrations of testosterone are necessary for normal cardiac development, but low testosterone is associated with adverse cardiac effects in men, while high testosterone is correlated with increased risk of cardiovascular disease in men and women.
  4. Conditions unique to or predominant in women, such as pregnancy, menopause, and certain autoimmune diseases, are associated with alterations in sex hormone production and function and play a fundamental role in promoting cardiovascular disease in women.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1 This figure illustrates that the number of women who participated in randomized control trials is low in relation to the number of women who suffer from cardiovascular disease. Underrepresentation of women in biomedical research hinders our understanding of the pathophysiology of various cardiovascular diseases in women as compared to men. Importantly, it delays the development of therapeutic interventions that can specifically target the female patients with cardiovascular disease.

Figure 2 This figure illustrates the age-related changes in systolic and diastolic blood pressure from early childhood to adulthood. Sex differences in blood pressure, with men having higher blood pressures compared to women, are observed after puberty. This sexual dimorphism is evident until menopause.

Figure 3 This figure illustrates that LV mass and volumes vary with age and sex. Left ventricular mass (LV) mass increases during adolescence and declines in adulthood. Adolescent and adult males have greater LV mass compared to age-matched females, even after adjusting for body size (body surface area, BSA). End-diastolic volume (EDV) calculated as the endocardial volume at end-diastole increases during adolescence and early adulthood in males and declines thereafter but this trend was not observed in females. There are no sex differences in EDV during adolescence, but adult males have greater EDV compared to adult females.

Figure 4 This figure illustrates sex differences in age-related changes in circulating total and bioavailable estrogen. Bioavailable estrogen has rapid access to target tissues, while total estrogen comprises the fractions of estrogen that are bound to sex hormone binding globulin (SHBG) and the bioavailable form. Understanding the normal temporal changes in bioavailable estrogen may provide insight into the correlation between estrogen deficiency and sex differences in cardiovascular function and disease. In men, there is a small decrease in total estrogen with age, while bioavailable estrogen declines by 47% between 25 and 85 years of age. In women, both total and bioavailable estrogen decline in a similar manner and there is a large drop in both forms around the time of menopause.

Figure 5 Teaching points: Estrogen can induce its actions via nongenomic pathways that do not involve activation of nuclear estrogen receptors. Estrogen signaling via nongenomic mechanisms is rapid, involves estrogen receptors that are located in small invaginations of the plasma membrane (i.e., caveolae) and various intracellular signaling molecules such as kinases and phosphatases. In endothelial cells, the nongenomic estrogen signaling induces activation of kinases that leads to endothelial nitric oxide synthase (eNOS) phosphorylation and NO production. These events promote endothelium-dependent relation, and proliferation and migration of endothelial cells. In vascular smooth muscle cells, the nongenomic estrogen signaling induces phosphatase-mediated kinase inhibition that reduces vascular smooth muscle proliferation and migration.

Figure 6 Teaching points: The nongenomic actions of estrogen can be executed not only through the ER receptors that are localized in the plasma membrane but also through an orphan G-protein-coupled receptor, GPR30, also known as G protein-coupled estrogen receptor 1 (GPER-1). Signaling through this novel estrogen receptor induces vasodilation in the vasculature. Several studies in coronary arteries have indicated two different mechanisms for this action. Panel A illustrates an endothelium-independent mechanism that is mediated by a large conductance calcium-activated potassium channel, BK channel, which is expressed in coronary smooth muscle. Panel B illustrates an endothelium-dependent mechanism that involves activation of endothelial nitric oxide synthase (eNOS) and production of nitric oxide (NO) in vascular endothelial cells.

Figure 7 Teaching points: The presence of estrogen receptor subtypes, ERα and ERβ, has been demonstrated in male and female human hearts. Hearts from healthy men, however, have higher expression of ERβ mRNA as compared to age-matched healthy postmenopausal women. In aortic stenosis, there is upregulation of ERβ mRNA that is inversely correlated to factors causing hypertrophic responses. The percent increase of ERβ mRNA is greater in women as compared to men with aortic stenosis, indicating probably a better compensatory response in women.

Figure 8 This figure illustrates sex-related variation in the expression of 56 genes in mice with cardiomyocyte-specific deletion of ERα. These genes were associated with various transcriptional networks and receptor hubs like extracellular space and matrix, NOS signaling, relaxation of vascular smooth muscle cells, metabolic networks, and certain signaling pathways. That means ERα regulates these processes differentially in men and women.

Figure 9 Teaching points: Menopause and associated estrogen deficiency are considered risk factors of cardiovascular disease in women. Understanding the mechanism underlying the effects of estrogen on cardiac function after cardiac ischemia-reperfusion injury in animal models aids in the development of efficacious estrogen replacement interventions. In female mice that were ovariectomized, treatment with estradiol or an estrogen-dendrimer conjugate improved all cardiac recovery after ischemia-reperfusion injury.

Figure 10 Teaching points: Premenopausal women are less likely to suffer from coronary artery disease compared to age-matched men, potentially due to the protective effects of estrogen. This effect is lost after menopause. This figure illustrates that pre-treatment with estrogen potentiates coronary artery dilation in postmenopausal women with coronary artery disease but has no effect in age-matched men. Understanding the effects of exogenous estrogen on the coronary vasculature leads to development of better estrogen replacement strategies and provides insight into the differing responses to hormone replacement therapies between men and women.

Figure 11 This figure illustrates sex differences in age-related changes in circulating total and bioavailable testosterone. Bioavailable form of testosterone is either free or associated with albumin in the circulation and it has rapid access to target tissues. Understanding the temporal changes in bioavailable circulating testosterone is important because a decrease in total testosterone fails to explain the morbidities seen in men with advancing age. Notice that the decrease in total testosterone is only 29%, while that of bioavailable testosterone is twice (64%) in men with increasing age. On the other hand, the reductions in total and bioavailable testosterone are marginal in women with increasing age (15% and 28% respectively).

Figure 12 Teaching points: Hydrogen peroxide (H2S) is a gas that has vasodilatory effects. Testosterone-induced vasodilation, but not estrogen- and progesterone-induced dilation, involves H2S in aortic rings of male rats. These effects are associated with the ability of testosterone to promote H2S production.

Figure 13 This figure illustrates that women who had experienced a hypertensive disorder of pregnancy have a greater risk of developing cardiovascular disease later in life compared to women who had no complications during pregnancy. Understanding whether and how pregnancy complications lead to cardiovascular disease is important because it aids in early identification and management of women in high risk of developing cardiovascular complications later in life.

Figure 14 This figure illustrates that testosterone and estradiol differ between normal pregnant women and women with preeclampsia. In preeclampsia, a hypertensive disorder of pregnancy that is characterized by systemic inflammation, circulating testosterone is increased, estradiol is reduced, and the ratio of testosterone to estradiol is significantly higher compared to normal pregnancy. Expression of aromatase and 17β-HSD3, enzymes that facilitate the synthesis of estrogen and testosterone, respectively, differs between women with preeclampsia and women who experience preterm labor. Understanding the role of sex steroids in gestational complications, such as preeclampsia and preterm labor, will aid in the development of interventions to counteract or potentiate their effects.

Figure 15 This figure illustrates a nonlinear, J-shaped relationship, between number of live births and incident of death from cardiovascular disease. The risk of mortality from cardiovascular disease is exponentially increased in women who had experienced large number (> 6) of births. This risk is higher in women with no children as compared to women with two to five children; yet, it remains substantially lower compared to women with large parity.

 


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Sarika Chaudhari, Spencer C. Cushen, Oluwatobiloba Osikoya, Paresh A. Jaini, Rachel Posey, Keisa W. Mathis, Styliani Goulopoulou. Mechanisms of Sex Disparities in Cardiovascular Function and Remodeling. Compr Physiol 2018, 9: 375-411. doi: 10.1002/cphy.c180003