Uncovering a Mineralocorticoid Receptor–Dependent Adipose–Vascular Axis: Implications for Vascular Dysfunction in Obesity?

Obesity, insulin resistance, and type 2 diabetes mellitus (T2DM) are associated with increased levels of aldosterone and activation of cardiovascular mineralocorticoid receptors (MRs) contributing to hypertension and associated cardiovascular disease (CVD) (1). Large randomized controlled trials such as the Randomized Aldactone Evaluation Study (RALES), the Epleronone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS), and the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) have demonstrated the CVD-related mortality and morbidity benefits of MR antagonists, further implicating MR signaling as a key mediator of CVD (2). The actions of kidney MR signaling to increase cardiovascular and renal fibrosis and blood pressure is well known; however, recent research suggests that inappropriate activation of extrarenal MR signaling in vascular endothelial cells (ECs), vascular smooth muscle cells (VSMCs), immune cells, and adipocytes promotes insulin resistance, T2DM, and associated CVD (1,3,4). For example, in association with obesity and insulin resistance, perivascular and visceral adipose tissue (PVAT and VAT) is dysfunctional, in part, because of adipose MR activation (3). Furthermore, PVAT and VAT secrete aldosterone, the ligand for MRs in endothelial and smooth muscle cells, and this is increased in obesity (3,4). PVAT is a unique depot of adipose tissue that surrounds blood vessels to provide mechanical protection and helps regulate blood vessel tone (5,6). PVAT exerts divergent effects in different vascular beds, perhaps related to differences in fat constitution (5,6). For example, the thoracic aorta is surrounded by brown adipose tissue (BAT) and white adipose tissue (WAT), whereas the abdominal aorta is surrounded only by WAT (6). In rodents, the mesenteric artery is enmeshed in WAT, which is traditionally expanded in conditions of obesity and insulin resistance. Under normal physiological conditions, PVAT releases vasodilator substances such as adiponectin and adipocyte-derived relaxing factors that contribute to the maintenance of normal vascular tone (5,6). In pathological conditions such as obesity, however, enhanced MR signaling in PVAT and VAT activates NADPH oxidase–derived reactive oxygen species and releases proinflammatory adipokines such as visfatin, resistin, tumor necrosis factor-a, and interleukin-6, contributing to impaired vascular insulin metabolic signaling and vascular relaxation (3,7). Indeed, in the Framingham Heart Study (FHS), increased PVAT was an independent risk factor for CVD (8). The effect of PVAT to modulate vasodilation in health and disease is well established; however, much less is known about the impact of MRdependent adipose signaling on vascular constriction. One recent study demonstrated that coronary PVAT from obese swine augments coronary contractile responsiveness (9). In this issue of Diabetes, Nguyen Dinh Cat et al. (10) address this issue by evaluating the role of adipocyte-specific MR overexpression, previously shown to promote obesity and insulin resistance, in the regulation of mesenteric microvascular contractility. Increased adipocyte MR activation promoted an increase in adipose-derived hydrogen peroxide (H2O2), a vasodilatory reactive oxygen species, and impaired arteriolar vascular smooth muscle contractility involving upregulation of vascular redox–sensitive protein kinase G (PKG)-1, downregulation of redox-sensitive Rho kinase (ROCK) activity, and increased elastin content.