Paracrine Effects of Perivascular Adipose Tissue on Atherogenesis: Role of Extracellular Vesicles‐Mediated Intercellular Communications

Abstract

Background Development of atherosclerosis depends on the interaction between various factors. Type 2 diabetes accelerates these interactions and predisposes to rapid progression of atherosclerosis. Diminution of vasoprotective effects of perivascular adipose tissue (PVAT) in metabolic disorders suggests a molecular link between diabetes and atherosclerosis. Objectives To assess the paracrine role of the PVAT on the progression of diabetic atherosclerosis, via intercellular communications between PVAT and the underlying vasculature. Methods Periaortic adipose tissue from Type 2 diabetic (db/db) mice were transplanted around the right common carotid arteries of ApoE-/- mice, followed by 16 weeks of atherogenic diet. Carotid arteries and adipose tissues were assessed for lesion formation and inflammatory markers, respectively. Adipose stem cells (ASCs) from PVAT were treated with lipopolysaccharide (1µg/ml), palmitate (200µM), and high-glucose (42 mM) for 24 hrs (denoted as P-ASCs) to mimic type 2 diabetes-associated metabolic alterations. Small extracellular vesicles (sEV) were isolated from the conditioned media. Aortic vascular smooth muscle cells (SMCs) were incubated with ASC-derived sEV (25µg/ml). The migratory potential of SMCs was evaluated by wound healing assay. Results Histological analysis displayed accelerated atherogenic plaque formation with transplantation of type 2 diabetic PVAT around the carotid arteries of ApoE-/- mice, which is otherwise resistant to plaque formation. Pro-inflammatory markers were significantly increased in periaortic adipose tissue from db/db compared to WT. sEV secreted from P-ASCs greatly enhanced the SMC migration when compared with the control ASCs. Conclusions Our data shows type 2 diabetes-accelerated progression of atherosclerosis is mediated by PVAT-derived sEV.