LAUSR

Background: Perivascular adipose tissue (PVAT) possibly plays a pivotal role in the development of atherosclerosis through its direct local action to the vessels. However, its physiological and molecular mechanisms are less understood. Visceral and subcutaneous white adipose tissues exert a brown adipose tissue-like phenotype under specific conditions such as cold exposure, i.e. browning. We here investigated the pathophysiological role of browning of PVAT against the development of atherosclerosis after endovascular injury. Methods and Results: Endovascular injury was generated by wire insertion into the femoral artery of C57BL/6 female mice. Transcriptome analysis revealed robust upregulation of brown adipose tissue markers such as Ucp1 , Elovl3 , Cox8b and Cidea in injured arteries. Notably, administration of an atheroprotective agent, 17-beta estradiol, significantly inhibited these changes; Ucp1 was the most down-regulated gene by 17-beta estradiol administration in the entire gene set (log2-fold change = -6.58, false discovery rate = 0.003). Consistently, the upregulation of browning markers after endovascular injury and these inhibitions by 17-beta estradiol were confirmed in PVAT by quantitative real-time PCR, western blot and immunohistochemical staining. The present study also demonstrated that vascular injury promotes macrophage infiltration in PVAT accompanied with upregulation of inflammatory cytokine production. Furthermore, we confirmed spatiotemporal synchronicity between browning and inflammation in PVAT by immunohistochemical staining. Conclusions: We observed that endovascular injury elicits browning in PVAT accompanied with exacerbated inflammation, and that atheroprotective 17-beta estradiol strongly inhibits this phenomenon. These findings may provide novel insights into pathogenesis of the atherosclerosis.