Abstract
BackgroundThe 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 FindingsMembrane potential, vessel diameter and luminal pressure were recorded in 4th 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 (SKCa/IKCa) inhibition; with such activity being impaired in obesity. SKCa-IKCa 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. IKCa-mediated EDH contribution was increased in obesity, and associated with altered IKCa distribution and elevated expression. In contrast, the SKCa-dependent-EDH component was reduced in obesity. Inward-rectifying potassium channel (Kir) and Na+/K+-ATPase inhibition by barium/ouabain, respectively, attenuated and abolished EDH in arteries from control and obese rats, respectively; reflecting differential Kir expression and distribution. Although changes in medial properties occurred, obesity had no effect on myoendothelial gap junction density.Conclusion/SignificanceIn 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 IKCa and Na+/K+-ATPase, and decreased Kir underlie changes in the EDH mechanism.
Highlights
Obesity is at epidemic levels, with cardiovascular dysfunction being a common outcome [1]
The present study aimed to examine the effect of diet-induced obesity on endothelium-derived hyperpolarization (EDH)-mediated function and the underlying mechanisms in rat mesenteric artery with myogenic tone
General features of diet-induced obese rats The effect of dietary intervention on biochemical and metabolic parameters was characterized in control and obese rats
Summary
Obesity is at epidemic levels, with cardiovascular dysfunction being a common outcome [1]. Vascular tone refers to the balance between constrictor and dilator influences and is critical for the control of blood flow and pressure, and for normal cardiovascular function. Characterization of the EDH response in health and disease is critical, as such activity generally underlies the primary vasodilator mechanism in the smaller resistance vessels that are integral for control of vascular tone and blood flow [4,6,7]. 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
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
