Mechanisms of endothelial dysfunction in obesity-associated hypertension

Abstract

Obesity is strongly associated with high blood pressure, dyslipidemia, and type 2 diabetes. These conditions synergistically increase the risk of cardiovascular events. A number of central and peripheral abnormalities can explain the development or maintenance of high blood pressure in obesity. Of great interest is endothelial dysfunction, considered to be a primary risk factor in the development of hypertension. Additional mechanisms also related to endothelial dysfunction have been proposed to mediate the development of hypertension in obese individuals. These include: increase in both peripheral vasoconstriction and renal tubular sodium reabsorption, increased sympathetic activity and overactivation of both the renin-angiotensin system and the endocannabinoid system and insulin resistance. The discovery of new mechanisms regulating metabolic and vascular function and a better understanding of how vascular function can be influenced by these systems would facilitate the development of new therapies for treatment of obesity-associated hypertension.

Figure 1.. Mechanisms involved in obesity-associated hypertension. WAT = white adipose tissue; SNS = sympathetic nervous system; RAS = renin-angiotensin system.

Figure 2.. Putative mechanisms of endothelial dysfunction in obesity-associated hypertension. Decreased nitric oxide (NO) bioavailability as a consequence of uncoupled endothelial nitric oxide synthase (eNOS), a process in which eNOS generates superoxide (O₂⁻) instead of NO when the concentrations of either L-arginine (L-arg), the substrate of NOS, or tetrahydrobiopterin (BH₄), a cofactor of the enzyme, are depleted, may mediate endothelial dysfunction in obesity-associated hypertension. Increased reactive oxygen species generation as a consequence of increased NF oxidase and NF-κB activity and reduced superoxide dismutase (SOD) activity also contribute to decreasing NO bioavailability in this situation. Increased production of endothelium-derived contractile factors (EDCFs), including prostanoids (PGF_2α and TX₂), angiotensin II (Ang II) and endothelin I (ET-1) constitute additional mechanisms involved in endothelial dysfunction in obesity-associated hypertension. A potential role for perivascular adipose tissue (PVAT) in the vascular dysfunction of obesity has also been proposed. PVAT can reduce adenosine monophosphate-activated protein kinase (AMPK) activation and increase the NAD(P)H oxidase-induced O₂⁻ production leading to reduced NO production. AA = arachidonic acid; ACE = angiotensin-converting enzyme; COX = cyclooxygenase; EC = endothelial cells; ECE = endothelin-converting enzyme; NF-κB = nuclear factor κB; pET-1 = pro-endothelin 1; PGI₂ = prostaglandin I₂; VSMC = vascular smooth muscle cells; WAT = white adipose tissue.