Beiging of perivascular adipose tissue regulates its inflammation and vascular remodeling

Abstract

Although inflammation plays critical roles in the development of atherosclerosis, its regulatory mechanisms remain incompletely understood. Perivascular adipose tissue (PVAT) has been reported to undergo inflammatory changes in response to vascular injury. Here, we show that vascular injury induces 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 accumulate in PVAT, causing beiging phenotype change. Inhibition of PVAT beiging by genetically silencing PRDM16, a key regulator to beiging, exacerbates inflammation and vascular remodeling following injury. Conversely, activation of PVAT beiging attenuates inflammation and pathological vascular remodeling. Single-cell RNA sequencing reveals that beige adipocytes abundantly express neuregulin 4 (Nrg4) which critically regulate alternative macrophage activation. Importantly, significant beiging is observed in the diseased aortic PVAT in patients with acute aortic dissection. Taken together, vascular injury induces the beiging of adjacent PVAT with macrophage accumulation, where NRG4 secreted from the beige PVAT facilitates alternative activation of macrophages, leading to the resolution of vascular inflammation. Our study demonstrates the pivotal roles of PVAT in vascular inflammation and remodeling and will open a new avenue for treating atherosclerosis.

Coronary Artery Disease Risk GenePRDM16is Preferentially Expressed in Vascular Smooth Muscle Cells and a Potential Novel Regulator of Smooth Muscle Homeostasis

“…Together with previous study showing multiple CAD SNPs residing in SMCs-specific peaks at PRDM16 gene locus and are associated with PRDM16 expression 31 , we speculate that PRDM16 contributes to CAD progression mainly through regulating VSMC phenotype, although non-SMCs such as brown fat adipocytes and endothelial cells can be additional potential contributor to disease development [57][58][59][60] . Future studies are warranted to explore its function under pathological conditions by introducing vascular diseases, such as atherosclerosis, to Prdm16 iSM KO mice.…”

Perivascular Adipose Tissue and Vascular Smooth Muscle Tone: Friends or Foes?

“…This makes white PVAT of crucial importance because small vessels play a major role in the regulation of blood pressure compared to large vessels. Nevertheless, PVAT may either harbour beige adipocytes or undergoes beiging under certain pathophysiological stimuli [ 19 ]. Conversely, in adult humans, brown-like PVAT is nearly absent, and PVAT exhibits a white adipose tissue phenotype [ 24 ].…”

“…PVAT is now well recognized for its contribution to the regulation of vascular tone via outside-in signalling [ 3 , 5 ]. Moreover, PVAT is involved in all aspects of vascular pathophysiology because it modulates inflammation-associated vascular pathologies such as vascular remodelling, atherosclerosis, and obesity by secreting several adipokines, pro- and anti-inflammatory cytokines, and chemokines (for a review, see [ 17 , 18 , 19 ]).…”

Perivascular adipose tissue: Fine-tuner of vascular redox status and inflammation

“…Majority of PVATs, particularly those around thoracic aorta, display certain defining hallmarks of brown adipose tissue (BAT), including expression of thermogenic genes (e.g. Ucp-1 ), presence of numerous lipid droplets, and high mitochondrial content [ 6 ]. Besides, certain PVAT, predominantly mesenteric PVAT, is more-white adipose tissue (WAT)-like, due to lower expression of thermogenic genes like UCP-1, presence of larger lipid droplets, and low mitochondrial number [ 7 ].…”