Reduced Vascular Nitric Oxide–cGMP Signaling Contributes to Adipose Tissue Inflammation During High-Fat Feeding
- 1 December 2011
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Arteriosclerosis, Thrombosis, and Vascular Biology
- Vol. 31 (12), 2827-2835
- https://doi.org/10.1161/atvbaha.111.236554
Abstract
Objective— Obesity is characterized by chronic inflammation of adipose tissue, which contributes to insulin resistance and diabetes. Although nitric oxide (NO) signaling has antiinflammatory effects in the vasculature, whether reduced NO contributes to adipose tissue inflammation is unknown. We sought to determine whether (1) obesity induced by high-fat (HF) diet reduces endothelial nitric oxide signaling in adipose tissue, (2) reduced endothelial nitric oxide synthase (eNOS) signaling is sufficient to induce adipose tissue inflammation independent of diet, and (3) increased cGMP signaling can block adipose tissue inflammation induced by HF feeding. Methods and Results— Relative to mice fed a low-fat diet, an HF diet markedly reduced phospho-eNOS and phospho-vasodilator-stimulated phosphoprotein (phospho-VASP), markers of vascular NO signaling. Expression of proinflammatory cytokines was increased in adipose tissue of eNOS−/− mice. Conversely, enhancement of signaling downstream of NO by phosphodiesterase-5 inhibition using sildenafil attenuated HF-induced proinflammatory cytokine expression and the recruitment of macrophages into adipose tissue. Finally, we implicate a role for VASP, a downstream mediator of NO-cGMP signaling in mediating eNOS-induced antiinflammatory effects because VASP−/− mice recapitulated the proinflammatory phenotype displayed by eNOS−/− mice. Conclusion— These results imply a physiological role for endothelial NO to limit obesity-associated inflammation in adipose tissue and hence identify the NO-cGMP-VASP pathway as a potential therapeutic target in the treatment of diabetes.Keywords
This publication has 34 references indexed in Scilit:
- Alternative Macrophage Activation and MetabolismAnnual Review Of Pathology-Mechanisms Of Disease, 2011
- Macrophages, Inflammation, and Insulin ResistanceAnnual Review of Physiology, 2010
- The role of chemokines in recruitment of immune cells to the artery wall and adipose tissueVascular Pharmacology, 2009
- Mechanisms of obesity and related pathologies: The macro‐ and microcirculation of adipose tissueThe FEBS Journal, 2009
- eNOS, metabolic syndrome and cardiovascular diseaseTrends in Endocrinology & Metabolism, 2009
- Relaxing the actin cytoskeleton for adhesion and movement with Ena/VASPThe Journal of cell biology, 2008
- Improvement of vascular function by acute and chronic treatment with the PDE‐5 inhibitor sildenafil in experimental diabetes mellitusBritish Journal of Pharmacology, 2008
- Cytoskeleton assembly at endothelial cell–cell contacts is regulated by αII-spectrin–VASP complexesThe Journal of cell biology, 2008
- Cardiovascular roles of nitric oxide: A review of insights from nitric oxide synthase gene disrupted miceCardiovascular Research, 2007
- Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell functionThe Journal of Experimental Medicine, 2006