Sex/Gender- and Age-Related Differences in β-Adrenergic Receptor Signaling in Cardiovascular Diseases

Abstract

Sex differences in cardiovascular disease (CVD) are often recognized from experimental and clinical studies examining the prevalence, manifestations, and response to therapies. Compared to age-matched men, women tend to have reduced CV risk and a better prognosis in the premenopausal period. However, with menopause, this risk increases exponentially, surpassing that of men. Although several mechanisms have been provided, including sex hormones, an emerging role in these sex differences has been suggested for β-adrenergic receptor (β-AR) signaling. Importantly, β-ARs are the most important G protein-coupled receptors (GPCRs), expressed in almost all the cell types of the CV system, and involved in physiological and pathophysiological processes. Consistent with their role, for decades, βARs have been considered the first targets for rational drug design to fight CVDs. Of note, β-ARs are seemingly associated with different CV outcomes in females compared with males. In addition, even if there is a critical inverse correlation between β-AR responsiveness and aging, it has been reported that gender is crucially involved in this age-related effect. This review will discuss how β-ARs impact the CV risk and response to anti-CVD therapies, also concerning sex and age. Further, we will explore how estrogens impact β-AR signaling in women.

Estrogen downregulates CD73/adenosine axis hyperactivity via adaptive modulation PI3K/Akt signaling to prevent myocarditis and arrhythmias during chronic catecholamines stress

“…Chronic catecholamine stress is a risk factor for CVDs, and premenopausal women are less susceptible to developing than men [ 25 ]. This relative immunity has been attributed to the cardioprotective role of estrogen [ 8 ].…”

Hyperuricemia and Endothelial Function: Is It a Simple Association or Do Gender Differences Play a Role in This Binomial?

“…Estradiol can also increase sensitivity to vasodilatory factors, such as acetylcholine or prostaglandins, thus reducing the concentrations required to evoke similar vasodilatory responses [ 52 , 53 ]. In women of childbearing age, estradiol is associated with an increase in vascular relaxation, mainly mediated by NO [ 54 , 55 ]. Ethinylestradiol also attenuates vasoconstrictive responses to the infusion of noradrenaline in perimenopausal women [ 10 ].…”

Gender and Renal Insufficiency: Opportunities for Their Therapeutic Management?

“…Estradiol may also increase sensitivity to vasodilatory factors, such as acetylcholine or prostaglandins, thereby reducing the concentrations required to evoke similar vasodilatory responses [ 62 ]. However, after menopause, there is a reduction in the beneficial effect of female sex hormones on the adrenergic receptors, which causes an increased risk of hypertension in postmenopausal women [ 63 ]. Therefore, the mechanisms contributing to the greater vascular relaxation by estradiol consist of a greater bioavailability of NO associated with greater adrenergic sensitivity [ 63 ].…”

“…However, after menopause, there is a reduction in the beneficial effect of female sex hormones on the adrenergic receptors, which causes an increased risk of hypertension in postmenopausal women [ 63 ]. Therefore, the mechanisms contributing to the greater vascular relaxation by estradiol consist of a greater bioavailability of NO associated with greater adrenergic sensitivity [ 63 ].…”