Abstract 5169: Endovascular Injury Induces Rapid Phenotypic Changes in Perivascular Adipose Tissue

Abstract

Background: It was reported that the serum levels of circulating proinflammatory cytokines are increased in overweight people with enhanced accumulation of visceral fat. In contrast to visceral fat, little attention has been paid to the role of perivascular fat in the pathogenesis of obesity-associated diseases. Here, we investigated the effect of endovascular injury on the phenotype of perivascular fat. Methods and Results: First, endovascular injury significantly down-regulated adiponectin and up-regulated proinflammatory adipocytokines, TNF-alpha, IL-6, PAI-1 and MCP-1 within perivascular fat tissue in models of murine femoral artery wire injury and rat iliac artery balloon injury (p<0.05). Second, diet-induced obesity augmented endovascular injury-induced up-regulation of proinflammatory adipocytokines within perivascular fat tissue (p<0.05) and neointimal hyperplasia (p<0.05) compared with standard chow diet in wild-type mice. Third, up-regulation of proinflammatory adipocytokines within perivascular fat by endovascular injury was significantly blunted in TNF-alpha deficient mice (p<0.05). Neointima formation was attenuated in TNF-alpha deficient mice compared with wild-type mice (p<0.05). Furthermore, perivascular delivery of TNF-alpha to the femoral artery using osmotic minipump enhanced endovascular injury-induced up-regulation of proinflammatory adipocy-tokines within perivascular fat (p<0.05) and neointimal hyperplasia (p<0.05) compared with contralateral PBS delivered artery in TNF-alpha deficient mice. Fourth, conditioned medium from the coculture of 3T3L1-derived adipocyte and RAW264 macrophage stimulated rat vascular smooth muscle cells proliferation relative to the control medium from 3T3L1-derived adipocyte (p<0.05). Blockade of TNF-alpha in the co-culture using an anti-TNF-alpha neutralizing antibody reduced the stimulatory activity of the condition medium (p<0.05). Conclusions: Our findings indicate that endovascular injury induces rapid and marked changes in perivascular adipose tissue, mainly mediated by TNF-alpha. It is suggested that the phenotypic changes in perivascular adipose tissue may have a role in the pathogenesis of neointimal hyperplasia after angioplasty.