Diet-induced obesity impairs endothelium-derived hyperpolarization via altered potassium channel signaling mechanisms

Background

The vascular endothelium plays a critical role in the control of blood flow. Altered endothelium-mediated vasodilator and vasoconstrictor mechanisms underlie key aspects of cardiovascular disease, including those in obesity. Whilst the mechanism of nitric oxide (NO)-mediated vasodilation has been extensively studied in obesity, little is known about the impact of obesity on vasodilation to the endothelium-derived hyperpolarization (EDH) mechanism; which predominates in smaller resistance vessels and is characterized in this study.

Methodology/Principal Findings

Membrane potential, vessel diameter and luminal pressure were recorded in 4^th order mesenteric arteries with pressure-induced myogenic tone, in control and diet-induced obese rats. Obesity, reflecting that of human dietary etiology, was induced with a cafeteria-style diet (∼30 kJ, fat) over 16–20 weeks. Age and sexed matched controls received standard chow (∼12 kJ, fat). Channel protein distribution, expression and vessel morphology were determined using immunohistochemistry, Western blotting and ultrastructural techniques. In control and obese rat vessels, acetylcholine-mediated EDH was abolished by small and intermediate conductance calcium-activated potassium channel (SK_Ca/IK_Ca) inhibition; with such activity being impaired in obesity. SK_Ca-IK_Ca activation with cyclohexyl-2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine (CyPPA) and 1-ethyl-2-benzimidazolinone (1-EBIO), respectively, hyperpolarized and relaxed vessels from control and obese rats. IK_Ca-mediated EDH contribution was increased in obesity, and associated with altered IK_Ca distribution and elevated expression. In contrast, the SK_Ca-dependent-EDH component was reduced in obesity. Inward-rectifying potassium channel (K_ir) and Na⁺/K⁺-ATPase inhibition by barium/ouabain, respectively, attenuated and abolished EDH in arteries from control and obese rats, respectively; reflecting differential K_ir expression and distribution. Although changes in medial properties occurred, obesity had no effect on myoendothelial gap junction density.

Conclusion/Significance

In obese rats, vasodilation to EDH is impaired due to changes in the underlying potassium channel signaling mechanisms. Whilst myoendothelial gap junction density is unchanged in arteries of obese compared to control, increased IK_Ca and Na⁺/K⁺-ATPase, and decreased K_ir underlie changes in the EDH mechanism.