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Obesity and insulin resistance stiffen the vasculature, with females appearing to be more adversely affected. As augmented arterial stiffness is an independent predictor of cardiovascular disease (CVD), the increased predisposition of women with obesity and insulin resistance to arterial stiffening may explain their heightened risk for CVD. However, the cellular mechanisms by which females are more vulnerable to arterial stiffening associated with obesity and insulin resistance remain largely unknown. In this study, we provide evidence that female mice are more susceptible to Western diet–induced endothelial cell stiffening compared with age-matched males. Mechanistically, we show that the increased stiffening of the vascular intima in Western diet–fed female mice is accompanied by enhanced epithelial sodium channel (ENaC) activity in endothelial cells (EnNaC). Our data further indicate that: (i) estrogen signaling through estrogen receptor α (ERα) increases EnNaC activity to a larger extent in females compared with males, (ii) estrogen-induced activation of EnNaC is mediated by the serum/glucocorticoid inducible kinase 1 (SGK-1), and (iii) estrogen signaling stiffens endothelial cells when nitric oxide is lacking and this stiffening effect can be reduced with amiloride, an ENaC inhibitor. In aggregate, we demonstrate a sexual dimorphism in obesity-associated endothelial stiffening, whereby females are more vulnerable than males. In females, endothelial stiffening with obesity may be attributed to estrogen signaling through the ERα–SGK-1–EnNaC axis, thus establishing a putative therapeutic target for female obesity-related vascular stiffening.

The role of mineralocorticoids in the development of cardiovascular disease (CVD), cardiometabolic syndrome, type 2 diabetes mellitus, chronic kidney disease (CKD), and hypertension is a growing field of interest. Aldosterone, mainly through nongenomic actions that result in proliferation, fibrosis, inflammation, and tissue remodeling, has been linked to CVD and CKD. Increased circulating aldosterone is also associated with insulin resistance and impaired glucose homeostasis that contribute to the development of endothelial dysfunction, atherosclerosis, and kidney disease. Aldosterone-induced oxidative stress and inflammation play a key role in impairing insulin signaling. Mineralocorticoid receptor blockade restores insulin sensitivity, counterbalances the deleterious cardiovascular and renal effects of aldosterone, and emerges as an alternative to improve blockade of the renin-angiotensin-aldosterone system, which potentially could contribute to reduce the burden of CVD and CKD.

The dramatic increase in the prevalence of obesity worldwide represents one of the most important challenges of modern medicine, owing to its myriad related complications-in particular cardiovascular disease, the leading cause of death worldwide. Originating from early studies with Cannabis sativa, the active compound of marijuana, there has been an impressive progress in the knowledge about the endocannabinoid network, leading to the identification of specific pathways that modulate feeding behavior. The effects of endocannabinoids are not limited to the central nervous system, but also include peripheral tissues. Experimental and clinic trials have demonstrated the efficacy of endocannabinoid antagonists in the management of obesity and the cardiometabolic syndrome. Better understanding of the mechanisms underlying obesity will lead to development of more active and specific agents, which surely will enlarge the role of this efficacious alternative for management of obesity.

Diabetes mellitus confers a high risk of cardiovascular morbidity and mortality and requires aggressive management of all cardiovascular risk factors, including diabetic dyslipidemia. Although levels of low-density lipoprotein cholesterol are often normal or only slightly elevated in persons with diabetes, lipid-altering therapy with statins has been shown in large, randomized, controlled trials to decrease the risk of cardiovascular complications in this patient population. A target low-density lipoprotein cholesterol level of