Abstract 354: Beiging Of Perivascular Adipose Tissue Regulates Its Inflammation And Vascular Remodeling

Abstract

Background: Inflammation plays a primordial role in atherosclerosis. Perivascular adipose tissue (PVAT) that surrounds the vasculature has been reported to undergo phenotypic changes in response to vascular inflammation. However, regulatory roles of PVAT in vascular inflammation and subsequent pathological remodeling remain unclear. Methods and Results: Endovascular injury was generated by wire insertion into the mice femoral artery. Here, we showed that vascular injury induced the beiging (brown adipose tissue-like phenotype change) of PVAT, which fine-tunes inflammatory response and thus vascular remodeling as a protective mechanism. In a mouse model of endovascular injury, macrophages accumulated in PVAT, causing beiging phenotype change. Inhibition of PVAT beiging by adipose tissue-specific genetic ablation of PRDM16, a key regulator to beiging, exacerbated inflammation and vascular remodeling following injury. Local knockdown of Prdm16 in perivascular tissues of wild-type mice using small interfering RNA similarly exacerbated inflammation and vascular remodeling. Conversely, activation of PVAT beiging attenuated inflammation and pathological vascular remodeling. Single-cell RNA sequencing revealed that beige adipocytes abundantly expressed neuregulin 4 ( Nrg4 ) which critically regulated alternative macrophage activation. Furthermore, Nrg4 knockdown abolished the PVAT-mediated anti-inflammatory effects on macrophages. Importantly, significant beiging was observed in the diseased aortic PVAT in patients with acute aortic dissection. Conclusions: Endovascular injury induced the beiging of adjacent PVAT with macrophage accumulation, where NRG4 secreted from the beige PVAT facilitated alternative activation of macrophages, leading to the resolution of vascular inflammation. Our study demonstrated the pivotal roles of PVAT in vascular inflammation and remodeling and will open a new avenue for treating atherosclerosis.