title: Obesity up-regulates intermediate conductance calcium-activated potassium channels and myoendothelial gap junctions to maintain endothelial vasodilator function.
abstract: The mechanisms involved in altered endothelial function in obesity-related cardiovascular disease are poorly understood. This study investigates the effect of chronic obesity on endothelium-dependent vasodilation and the relative contribution of nitric oxide (NO), calcium-activated potassium channels (K(Ca)), and myoendothelial gap junctions (MEGJs) in the rat saphenous artery. Obesity was induced by feeding rats a cafeteria-style diet (∼30 kJ as fat) for 16 to 20 weeks, with this model reflecting human dietary obesity etiology. Age- and sex-matched controls received standard chow (∼12 kJ as fat). Endothelium-dependent vasodilation was characterized in saphenous arteries by using pressure myography with pharmacological intervention, Western blotting, immunohistochemistry, and ultrastructural techniques. In saphenous artery from control, acetylcholine (ACh)-mediated endothelium-dependent vasodilation was blocked by NO synthase and soluble guanylate cyclase inhibition, whereas in obese rats, the ACh response was less sensitive to such inhibition. Conversely, the intermediate conductance K(Ca) (IK(Ca)) blocker 1-[(2-chlorophenyl)diphenyl-methyl]-1H pyrazole attenuates ACh-mediated dilation in obese, but not control, vessels. In a similar manner, putative gap junction block with carbenoxolone increased the pEC(50) for ACh in arteries from obese, but not control, rats. IK1 protein and MEGJ expression was up-regulated in the arteries of obese rats, an observation absent in control. Addition of the small conductance K(Ca) blocker apamin had no effect on ACh-mediated dilation in either control or obese rat vessels, consistent with unaltered SK3 expression. Up-regulation of distinct IK(Ca)- and gap junction-mediated pathways at myoendothelial microdomain sites, key mechanisms for endothelial-derived hyperpolarization-type activity, maintains endothelium-dependent vasodilation in diet-induced obese rat saphenous artery. Plasticity of myoendothelial coupling mechanisms represents a significant potential target for therapeutic intervention.
authors.affiliation: Department of Pharmacology, School of Medical Sciences, University of New South Wales, Sydney, NSW, 2052, Australia.
authors.forename: Preet S
authors.initials: PS
authors.lastname: Chadha
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: Haddock
authors.forename: Lauren
authors.initials: L
authors.lastname: Howitt
authors.forename: Margaret J
authors.initials: MJ
authors.lastname: Morris
authors.forename: Tim V
authors.initials: TV
authors.lastname: Murphy
authors.forename: T Hilton
authors.initials: TH
authors.lastname: Grayson
authors.forename: Shaun L
authors.initials: SL
authors.lastname: Sandow
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure; D017629:Gap Junctions / Q000378:metabolism* / Q000502:physiology / Q000648:ultrastructure; D007150:Immunohistochemistry; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000819:agonists / Q000096:biosynthesis*; D008297:Male; D008854:Microscopy, Electron; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000502:physiology / Q000648:ultrastructure; D009213:Myography; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
chemical_list: D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D014662:Vasoconstrictor Agents