Cellular mechanisms underlying obesity-induced arterial stiffness

Abstract

Obesity is an emerging pandemic driven by consumption of a diet rich in fat and highly refined carbohydrates (a Western diet) and a sedentary lifestyle in both children and adults. There is mounting evidence that arterial stiffness in obesity is an independent and strong predictor of cardiovascular disease (CVD), cognitive functional decline, and chronic kidney disease. Cardiovascular stiffness is a precursor to atherosclerosis, systolic hypertension, cardiac diastolic dysfunction, and impairment of coronary and cerebral flow. Moreover, premenopausal women lose the CVD protection normally afforded to them in the setting of obesity, insulin resistance, and diabetes, and this loss of CVD protection is inextricably linked to an increased propensity for arterial stiffness. Stiffness of endothelial and vascular smooth muscle cells, extracellular matrix remodeling, perivascular adipose tissue inflammation, and immune cell dysfunction contribute to the development of arterial stiffness in obesity. Enhanced endothelial cortical stiffness decreases endothelial generation of nitric oxide, and increased oxidative stress promotes destruction of nitric oxide. Our research over the past 5 years has underscored an important role of increased aldosterone and vascular mineralocorticoid receptor activation in driving development of cardiovascular stiffness, especially in females consuming a Western diet. In this review the cellular mechanisms of obesity-associated arterial stiffness are highlighted.

Keywords: Western diet; cardiorenal metabolic syndrome; cardiovascular disease; cardiovascular stiffness.

Fig. 1.

Causes and consequences of obesity-associated arterial stiffness. RAAS, renin-angiotensin-aldosterone system; SNS, sympathetic nervous system; M1 and M2, macrophages; IL-10, interleukin 10; Treg, regulatory T cell; Th1 and Th17, T helper 1 and 17 cells; ER, endoplasmic reticulum; eNOS, endothelial nitric oxide synthase; PAI-1, plasminogen activator inhibitor 1; TPA, tissue plasminogen activator; CVD, cardiovascular disease; CKD, chronic kidney disease.

Fig. 2.

Endothelial cell (EC)-macrophage-vascular smooth muscle cell interactions in obesity-associated arterial stiffness. Impaired insulin metabolic signaling in ECs leads to decreased activation of endothelial nitric oxide (NO) synthase (eNOS) and NO bioavailability. Increase in endothelial Na⁺ channel (EnNaC) activity occurs due to mineralocorticoid receptor (MR)-induced activation of serum/glucocorticoid regulated kinase 1 (SGK1) and increased EnNaC expression, which result in increased influx of Na⁺ and polymerization of F actin, leading to endothelial cortical stiffness. This leads to impaired flow-mediated release of NO. Increased oxidative stress due to RAAS-induced activation of NADPH oxidase, xanthine oxidase, and mitochondrial oxidative stress results in increased destruction of NO. eNOS uncoupling leads to further decreases in bioavailable NO. Decreased bioavailable NO causes increased expression of adhesion molecules on ECs, favoring monocyte recruitment. Decreased bioavailable NO also results in macrophage (MΦ) activation, M1 macrophage polarization, and oxidative stress. This leads to further destruction of NO. Decreased bioavailable NO results in transglutaminase 2 (TG2) activation, which promotes collagen cross-linking and causes cortical stiffness, which impairs flow-mediated NO production. Decreased heme oxygense 1 (HO-1) activity further contributes to the decrease in bioavailable NO, thereby promoting arterial stiffness. ECM, extracellular matrix; ERK1/2, extracellular-regulated kinase 1/2; IRS-1, insulin receptor substrate-1; PI3K, phosphatidylinositol 3-kinase; ROS, reactive oxygen species; S6K1, S6 kinase 1.