Tumor Necrosis Factor-α Induces Aortic Intima-Media Thickening via Perivascular Adipose Tissue Inflammation

Abstract

Background/Aims: Neointimal thickening results from inflammation in association with vascular smooth muscle cell (VSMC) proliferation. We studied the role of perivascular adipose tissue (PVAT) on VSMC proliferation and intima-media thickening (IMT) in a rodent model of chronic inflammation. Methods: The abdominal aorta and surrounding PVAT of tumour necrosis factor (TNF)-α-injected mice were examined 28 days after administration. Plasma and PVAT cytokines were measured with Milliplex™ assays. Inflammatory cells were examined with immunofluorescence. Expression of transforming growth factor (TGF)-β1, matrix metalloproteinase (MMP)-2, MMP-9 and MMP-12 was examined with immunohistochemistry, immunoblotting and zymography. IMT was determined. Cell proliferation and TGF-β1 mRNA levels were examined after treating VSMC with PVAT homogenates ± MMP-2 inhibitors (batimastat, ARP 100 or TIMP-2) and SB-431542, a selective inhibitor of the TGF-β-type 1 receptor. Results: Significant increases in CD3, CD68, neutrophils, vascular cell adhesion molecule-1 and MMP-2 in PVAT, and TGF-β1 and IMT of the aorta of TNF-α-injected mice were observed. PVAT of TNF-α-injected mice significantly up-regulated TGF-β1 and increased cell proliferation in a dose-dependent manner and was attenuated by SB-431542, batimastat, ARP 100 and TIMP-2. Conclusions: Our study shows that chronic PVAT inflammation leads to MMP-mediated increase in TGF-β1 and hence VSMC proliferation.

Perivascular adipose tissue (PVAT) in atherosclerosis: a double-edged sword

“…Also, transplantation of PVAT derived from transgenic mice overexpressing adipose tissue-specific angiopoietin like 2 (ANGPTL2) accelerated neointimal hyperplasia induced by wire injury of the femoral artery, which was attenuated by transplantation of PVAT from ANGPTL2 −/− mice [ 189 ]. Moreover, inflamed PVAT increases VSMC proliferation in a TGF-β dependent manner, suggesting that TGF-β released from PVAT can potentiate neointima formation [ 190 ]. Furthermore, as reviewed elsewhere [ 136 ], PVAT-derived factors such as leptin, viafastin, TNF-α, IL-6 and IL-8, promote VSMC proliferation and migration.…”

PVAT and Its Relation to Brown, Beige, and White Adipose Tissue in Development and Function

“…Moreover, inflamed PVAT increases VSMC proliferation in a TGF-β dependent manner, suggesting that TGF-β released from PVAT can potentiate neointima formation (Moe et al, 2013 ) The PVAT transplantation approach has also been used to study the effects of PVAT-derived Angptl2 on the progression of neointimal hyperplasia after endovascular injury (Tian et al, 2013 ). Here, PVAT from mice over-expressing Angptl2 accelerate neointima formation, while PVAT from Angptl2 −/− mice attenuated it.…”

Perivascular Adipose Tissue in Vascular Function and Disease

“…34 Consistent with this, a recent study using a murine model of chronic inflammation via TNF-α injection found that PVAT inflammation led to MMP-mediated TGF-β production, resulting in neointima formation. 80 In addition, vascular injury has been reported to upregulate proinflammatory adipokines and downregulate anti-inflammatory adiponectin in PVAT in both mice and rats. 81 Furthermore, a high-fat diet in mice was found to induce a proinflammatory phenotype in the PVAT.…”