Perivascular adipose tissue dysfunction aggravates adventitial remodeling in obese mini pigs via NLRP3 inflammasome/IL-1 signaling pathway

Abstract

Perivascular adipose tissue (PVAT), a special type of adipose tissue, closely surrounds vascular adventitia and produces numerous bioactive substances to maintain vascular homeostasis. PVAT dysfunction has a crucial role in regulating vascular remodeling, but the exact mechanisms remain unclear. In this study, we investigated whether and how obesity-induced PVAT dysfunction affected adventitia remodeling in early vascular injury stages. Mini pigs were fed a high sugar and fat diet for 6 months to induce metabolic syndrome and obesity. In the mini pigs, left carotid vascular injury was then generated using balloon dilation. Compared with normal mini pigs, obese mini pigs displayed significantly enhanced vascular injury-induced adventitial responses, evidenced by adventitia fibroblast (AF) proliferation and differentiation, and adventitia fibrosis, as well as exacerbated PVAT dysfunction characterized by increased accumulation of resident macrophages, particularly the M1 pro-inflammatory phenotype, increased expression of leptin and decreased expression of adiponectin, and production of pro-inflammatory cytokines interleukin (IL)-1β and IL-18. Primary AFs cultured in PVAT-conditioned medium from obese mini pigs also showed significantly increased proliferation and differentiation. We further revealed that activated nod-like receptor protein 3 (NLRP3) inflammasome and its downstream products, i.e., IL-1 family members such as IL-1β and IL-18 were upregulated in the PVAT of obese mini pigs; PVAT dysfunction was also demonstrated in preadipocytes treated with palmitic acid. Finally, we showed that pretreatment with IL-1 receptor (IL-1R) antagonist or IL-1R knockdown blocked AF proliferation and differentiation in AFs cultured in PVAT-conditioned medium. These results demonstrate that obesity-induced PVAT dysfunction aggravates adventitial remodeling after early vascular injury with elevated AF proliferation and differentiation via activating the NLRP3/IL-1 signaling pathway.

Adipose Tissue Macrophage Polarization in Healthy and Unhealthy Obesity

“…Pro-inflammatory perivascular AT signaling is initiated by decreased nitric oxide production, increased reactive oxygen species, and pro-inflammatory cytokines released by the dysfunctional endothelium, vascular smooth muscle cells, or vascular macrophages ( 155 ). In MUO individuals, dysfunctional perivascular AT alterations stem from adipocyte hypertrophy, hypoxia, oxidative stress, and pro-inflammatory macrophage infiltration ( 158 , 159 ). These data suggest that MHO perivascular AT successfully facilitates glucose uptake while promoting anti-inflammatory macrophage accumulation.…”

Recent Developments in Vascular Adventitial Pathobiology

“…81 PVAT dysfunction is promoted by vascular injury, aging, obesity, and metabolic syndrome, and may impact adventitial remodeling during the early stages of vascular injury. 82 Communication between cells in the PVAT and cells residing in the other layers of the blood vessel wall occurs through the VV or through paracrine signaling. 83 PVAT dysfunction can be induced by obesity in minipigs with left carotid vascular injury.…”

“…83 PVAT dysfunction can be induced by obesity in minipigs with left carotid vascular injury. 82 This results in increased fibroblast proliferation and differentiation, as well as increased local inflammation characterized by the accumulation of proinflammatory macrophages, leptin, and proinflammatory cytokine IL-1b and IL-18. These changes have been shown to be induced by the nod-like receptor protein 3 inflammasome pathway.…”

Intrinsic Exercise Capacity and Mitochondrial DNA Lead to Opposing Vascular-Associated Risks

“…However, it has been shown that PVAT dysfunction intensified adventitial remodeling in obese/metabolic syndrome induced mini pigs. 44 Interestingly, we observed that the presence of HCR M-PVAT had a restorative impact on LCR MRA relaxation to acetylcholine. Adipose tissue transplantation as a therapeutic is a developing field of study.…”