Insulin resistance adipocyte-derived exosomes aggravate atherosclerosis by increasing vasa vasorum angiogenesis in diabetic ApoE-/- mice

Background: Vasa vasorum (VV) angiogenesis is increased in type 2 diabetes mellitus (T2DM) and may promote atherosclerotic plaque rupture. We sought to determine whether insulin resistance adipocyte-derived exosomes (IRADEs) played a major role in modulating VV angiogenesis and the mechanisms involved. Methods: The characterization of IRADEs was performed by electron microscopy, NTA (Nanoparticle Tracking Analysis) and western blot. The cellular effects of IRADEs on angiogenesis were explored in human umbilical vein endothelial cells (HUVECs) and murine aortic endothelial cells (MAECs) in vitro. The roles of IRADEs in angiogenesis were demonstrated with aortic ring and matrigel plug assays ex vivo and the plaque burden, plaque stability and angiogenesis-related protein expression in vivo were evaluated by ultrasonography, immunohistochemistry and western blot. Results: The IRADEs had a cup-shaped morphology, could be taken up by HUVECs and atherosclerotic plaques, and promoted tube formation by shh in vitro. In the aortic ring and matrigel plug assays, angiogenesis was significantly increased in the IRADEs group. Exogenously administered shh-containing IRADEs increased VV angiogenesis, the plaque burden, the vulnerability index and the expression of angiogenesis-related factors, whereas these effects were attenuated by silencing shh in IRADEs. Conclusions: In conclusion, IRADEs promote plaque burden and plaque vulnerability partly by inducing VV angiogenesis, which occurs partly through shh. Accordingly, the application of IRADEs may serve as a novel therapeutic approach to treat diabetic atherosclerosis. (c) 2018 Elsevier B.V. All rights reserved.