Perivascular adipose tissue modulates carotid plaque formation induced by disturbed flow in mice

Abstract

Objective: Emerging evidence shows that perivascular adipose tissue (PVAT) is crucially involved in inflammation and cardiovascular diseases. However, controversial results have been reported regarding the effect of PVAT in atherosclerosis. This study aimed to determine the role of PVAT in disturbed blood flow (d-flow)-induced carotid plaque formation.

Methods: ApoE^-/- male mice underwent partial carotid ligation (PCL) to induce d-flow in the left carotid artery (LCA) and were fed a high-fat diet for 2 weeks. Oil Red O and hematoxylin and eosin stains were used to determine adipose tissue. Thoracic PVAT from ApoE^-/- or wild-type female mice were transplanted to the LCA of PCL-treated ApoE^-/- mice. Carotid arteries were stained with Sudan IV to detect atherosclerotic lesions. Quantitative real-time reverse transcription polymerase chain reaction and immunofluorescence staining were performed to assess macrophage infiltration.

Results: By 2 weeks of the high-fat diet after PCL surgery, de novo adipose tissue was formed around the ligated LCA, where atherosclerotic plaques were also observed. Quantitative real-time reverse transcription polymerase chain reaction analysis of the newly formed PVAT revealed a similar transcription profile to native PVAT. Treatment with bisphenol A diglycidyl ether, a peroxisome proliferator-activated receptor γ inhibitor, diminished PVAT formation but increased plaque size and macrophage infiltration. Transplantation of thoracic PVAT from wild-type mice (PVAT-T^WT) rather than from ApoE^-/- mice (PVAT-T^ApoE-/-) nearly abrogated LCA plaque macrophage content without affecting plaque size. Mechanistically, PVAT-T^ApoE-/- showed higher messenger RNA levels of inflammatory cytokines compared with PVAT-T^WT.

Conclusions: Our findings suggest that regulated PVAT formation may confer protection against atherosclerosis-prone shear stress, probably through attenuation of focal inflammation.

Keywords: Atherosclerosis; Disturbed flow; Inflammation; Perivascular adipose tissue; Transplantation.