The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China.
Department of Geriatric Medicine, Qilu Hospital of Shandong University, Key Laboratory of Cardiovascular Proteomics of Shandong Province, Qilu Hospital of Shandong University, China.
Int J Cardiol. 2018 Aug 15;265:181-187. doi: 10.1016/j.ijcard.2018.04.028. Epub 2018 Apr 9.
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.
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.
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.
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.
血管外膜血管生成（VV）在 2 型糖尿病（T2DM）中增加，可能促进动脉粥样硬化斑块破裂。我们试图确定胰岛素抵抗脂肪细胞衍生的外泌体（IRADES）是否在调节 VV 血管生成及其相关机制中起主要作用。
通过电子显微镜、NTA（纳米颗粒跟踪分析）和 Western blot 对 IRADEs 进行表征。在体外研究 IRADEs 对人脐静脉内皮细胞（HUVECs）和小鼠主动脉内皮细胞（MAECs）血管生成的细胞作用。通过主动脉环和基质胶塞实验在体内证明 IRADEs 在血管生成中的作用，并通过超声、免疫组织化学和 Western blot 评估斑块负担、斑块稳定性和体内与血管生成相关的蛋白表达。
IRADES 具有杯形形态，可被 HUVECs 和动脉粥样硬化斑块摄取，并在体外促进 shh 诱导的管形成。在主动脉环和基质胶塞实验中，IRADES 组的血管生成明显增加。外源性给予含有 shh 的 IRADEs 增加了 VV 血管生成、斑块负担、易损性指数和血管生成相关因子的表达，而在 IRADEs 中沉默 shh 则减弱了这些作用。
总之，IRADES 通过诱导 VV 血管生成促进斑块负担和斑块易损性，部分通过 shh 发生，因此，IRADES 的应用可能成为治疗糖尿病性动脉粥样硬化的一种新的治疗方法。
