Endovascular Injury Induces Rapid Phenotypic Changes in Perivascular Adipose Tissue

Abstract

Objective— Accumulating evidence suggests that adipose tissue not only stores energy but also secretes various bioactive substances called adipocytokines. Periadventitial fat is distributed ubiquitously around arteries throughout the body. It was reported that inflammatory changes in the periadventitial fat may have a direct role in the pathogenesis of vascular diseases accelerated by obesity. We investigated the effect of endovascular injury on the phenotype of perivascular fat. Methods and Results— Endovascular injury significantly upregulated proinflammatory adipocytokines and downregulated adiponectin within periadventitial fat tissue in models of mouse femoral artery wire injury and rat iliac artery balloon injury. Genetic disruption of tumor necrosis factor (TNF)-α attenuated upregulation of proinflammatory adipocytokine expression, with reduced neointimal hyperplasia after vascular injury. Local delivery of TNF-α to the periadventitial area enhanced inflammatory adipocytokine expression, which was associated with augmented neointimal hyperplasia in TNF-α-deficient mice. Conditioned medium from a coculture of 3T3-L1 and RAW264 cells stimulated vascular smooth muscle cell proliferation. An anti-TNF-α neutralizing antibody in the coculture abrogated the stimulating effect of the conditioned medium. Conclusion— Our findings indicate that endovascular injury induces rapid and marked changes in perivascular adipose tissue, mainly mediated by TNF-α. It is suggested that the phenotypic changes in perivascular adipose tissue may have a role in the pathogenesis of neointimal hyperplasia after angioplasty.