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.

Keywords: G protein-coupled receptors; cardiovascular disease; sex differences; β-adrenergic receptor.

Figure 1

Schematic representation of β-adrenergic receptor (AR)-mediated induction of protein kinase A (PKA) and PKG downstream Gs and Gi protein activation. β1-, β2-, β3-, and the putative β4-AR are coupled to the stimulatory G proteins (Gs), while only β2- and β3-AR are also coupled to the inhibitory G proteins (Gi). Upon ligand binding (catecholamine, CA), Gs proteins activate the adenylate cyclase (AC) on the plasma membrane leading to the generation of Cyclic Adenosine Monophosphate (cAMP), with subsequent activation of PKA, that in turn phosphorylates several key factors, including the PKB (Akt), with the subsequent activation of the endothelial nitric oxide synthase (eNOS). Of note, eNOS activation increases the generation of NO that stimulates the soluble guanylate cyclase (sGC) to produce cGMP and PKG activation. Notably, following the Gi signaling pathway activation, β2- and β3-AR can give rise to NO via both eNOS and neuronal NOS (nNOS), thus leading to PKG induction. Gs—pathway in orange; Gi—pathway in green. Black arrows: Gs and Gi pathway.

Figure 2

Potential effects of estrogen or phytoestrogen therapy on sympathetic nervous system (SNS) hyperactivity in postmenopausal women. Increased SNS activity in postmenopausal women induces catecholamine secretion from the chromaffin cells of the adrenal medulla (~80% epinephrine (E) and 20% norepinephrine [NE]), or the postganglionic sympathetic fibers (~80% NE and 20% E), resulting in increased circulating catecholamine levels, accelerating the risk of adverse vascular and cardiac effects. Estrogen or phytoestrogen therapies may inhibit SNS overactivation, preserving β-adrenergic receptors (β-Ars) responsiveness and density, and therefore ameliorating most of the cardiovascular disease (CVD) risk factors.