Sex–Gender Disparities in Cardiovascular Diseases: The Effects of Estrogen on eNOS, Lipid Profile, and NFATs During Catecholamine Stress

Abstract

Cardiovascular diseases (CVDs) characterized by sex–gender differences remain a leading cause of death globally. Hence, it is imperative to understand the underlying mechanisms of CVDs pathogenesis and the possible factors influencing the sex–gender disparities in clinical demographics. Attempts to elucidate the underlying mechanisms over the recent decades have suggested the mechanistic roles of estrogen in modulating cardioprotective and immunoregulatory effect as a factor for the observed differences in the incidence of CVDs among premenopausal and post-menopausal women and men. This review from a pathomechanical perspective aims at illustrating the roles of estrogen (E2) in the modulation of stimuli signaling in the heart during chronic catecholamine stress (CCS). The probable mechanism employed by E2 to decrease the incidence of hypertension, coronary heart disease, and pathological cardiac hypertrophy in premenopausal women are discussed. Initially, signaling via estrogen receptors and β-adrenergic receptors (βARs) during physiological state and CCS were summarized. By reconciling the impact of estrogen deficiency and hyperstimulation of βARs, the discussions were centered on their implications in disruption of nitric oxide synthesis, dysregulation of lipid profiles, and upregulation of nuclear factor of activated T cells, which induces the aforementioned CVDs, respectively. Finally, updates on E2 therapies for maintaining cardiac health during menopause and suggestions for the advancement treatments were highlighted.

Estrogen Protects Vasomotor Functions in Rats During Catecholamine Stress

“…Therefore, during CCS, the vascular homeostatic function is disrupted and builds up the arterial pressure, thereby causing hypertension. Alternatively, (20,30,31).…”

“…Therefore, during CCS, the vascular homeostatic function is disrupted and builds up the arterial pressure, thereby causing hypertension. Alternatively, E 2 utilizes multiple mechanisms such as upregulating NO via facilitating eNOS activities and signaling via Angiotensin II receptor type 2 and Mas receptor to ensure vasodilation ( 20 , 30 , 31 ).…”

“…This finding adds to the mounting evidence suggesting that E 2 is essential for effective lipid metabolism. These studies showed that by modulating the activities and expression of low-density lipoprotein receptors (LDLR), scavenger receptor class B type 1 (SR-B1), and proprotein convertase subtilisin/kexin type 9 (PCSK9), E 2 helps to maintain a healthy balance in the lipid profile by keeping circulating levels of high-density lipoprotein (HDL) high and low-density lipoprotein receptors (LDL) low ( 20 , 32 , 33 ) However, the absence of E 2 permits a disorder in lipid metabolism, and hence, LDL level increases excessively ( 34 ). This results in the deposition of the bad lipid (LDL) in and around organs and vascular tissues in the form of adipose, thereby causing bodyweight gains.…”

“…Generally, clinical case reports have demonstrated that premenopausal women's blood pressures are lower than that of men of the same age; however, during menopause, the blood pressure of women increases significantly, which increases the incidence of hypertension ( 35 ). Hence, besides aging, E 2 deficiency during stress has been suggested as a risk factor for women ( 20 ). Therefore, we sort to confirm this in our animal models, and the results obtained were consistent with earlier findings ( 35 ).…”

“…Earlier studies have demonstrated that estrogen stimulates endothelial NO synthase (eNOS) and triggers the production and release of NO, an essential vasodilator ( 19 , 20 ). Also, estrogen has been shown to promote the growth and repair of injured cells ( 21 , 22 ).…”