Abstract
Impaired vascular function, manifested by an altered ability of the endothelium to release endothelium-derived relaxing factors and endothelium-derived contracting factors, is consistently reported in obesity. Considering that the endothelium plays a major role in the relaxant response to the cannabinoid agonist anandamide, the present study tested the hypothesis that vascular relaxation to anandamide is decreased in obese rats. Mechanisms contributing to decreased anandamide-induced vasodilation were determined. Resistance mesenteric arteries from young obese Zucker rats (OZRs) and their lean counterparts (LZRs) were used. Vascular reactivity was evaluated in a myograph for isometric tension recording. Protein expression and localization were analyzed by Western blotting and immunofluorescence, respectively. Vasorelaxation to anandamide, acetylcholine, and sodium nitroprusside, as well as to CB1, CB2, and TRPV1 agonists was decreased in endothelium-intact mesenteric arteries from OZRs. Incubation with an AMP-dependent protein kinase (AMPK) activator or a fatty acid amide hydrolase inhibitor restored anandamide-induced vascular relaxation in OZRs. CB1 and CB2 receptors protein expression was decreased in arteries from OZRs. Incubation of mesenteric arteries with anandamide evoked endothelial nitric oxide synthase (eNOS), AMPK and acetyl CoA carboxylase phosphorylation in LZRs, whereas it decreased phosphorylation of these proteins in OZRs. In conclusion, obesity decreases anandamide-induced relaxation in resistance arteries. Decreased cannabinoid receptors expression, increased anandamide degradation, decreased AMPK/eNOS activity as well as impairment of the response mediated by TRPV1 activation seem to contribute to reduce responses to cannabinoid agonists in obesity.
Highlights
Obesity is a major public health problem worldwide [1,2]
Reduced cannabinoid receptors expression, decreased anandamide-induced activation of AMP-dependent protein kinase (AMPK) and endothelial nitric oxide synthase (eNOS), increased degradation of anandamide as well as impairment of the response mediated by TRPV1 activation might be involved in the decreased response to anandamide in obese Zucker rats (OZRs)
Blood pressure (BP) and glucose levels were similar between lean Zucker rats (LZRs) and OZRs, OZRs displayed higher body weight and fat mass compared with age-matched LZRs
Summary
Obesity is a major public health problem worldwide [1,2]. This condition is considered one of the main risk factors for the increased morbidity and mortality from hypertension, dyslipidemia, type 2 diabetes, heart failure, stroke, and coronary artery disease [3]. The endocannabinoid system comprises the endocannabinoids, the enzymes involved in their biosynthesis and degradation and the G protein-coupled receptors (CB1 and CB2) that mediate their effects [11,12,13,14] This system plays an important role in the central and peripheral regulation of energy homeostasis, lipid metabolism, and fat accumulation [15]
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