Yu Shi-Ran, Cui Yu-Xia, Song Zi-Qi, Li Su-Fang, Zhang Chun-Ying, Song Jun-Xian, Chen Hong
Department of Cardiology, Center for Cardiovascular Translational Research, Beijing Key Laboratory of Early Prediction and Intervention of Acute Myocardial Infarction, Peking University People's Hospital, Beijing, China.
Front Physiol. 2022 May 9;13:850298. doi: 10.3389/fphys.2022.850298. eCollection 2022.
In recent years, the function of the lymphatic system in atherosclerosis has attracted attention due to its role in immune cell trafficking, cholesterol removal from the periphery, and regulation of the inflammatory response. However, knowledge of the mechanisms regulating lymphangiogenesis and lymphatic function in the pathogenesis of atherosclerosis is limited. Endothelial microparticles carrying circulating microRNA (miRNA)s are known to mediate cell-cell communication, and our previous research showed that miRNA-19b in EMPs (EMP) was significantly increased in circulation and atherosclerotic vessels, and this increase in EMP promoted atherosclerosis. The present study investigated whether atherogenic EMP influences pathological changes of the lymphatic system in atherosclerosis. We first verified increased miR-19b levels and loss of lymphatic system function in atherosclerotic mice. Atherogenic western diet-fed ApoE mice were injected with phosphate-buffered saline, EMPs carrying control miRNA (EMP), or EMP intravenously. The function and distribution of the lymphatic system was assessed via confocal microscopy, Evans blue staining, and pathological analysis. The results showed that lymphatic system dysfunction existed in the early stage of atherosclerosis, and the observed pathological changes persisted at the later stage, companied by an increased microRNA-19b level. In ApoE mice systemically treated with EMP, the distribution, transport function, and permeability of the lymphatic system were significantly inhibited. experiments showed that miRNA-19b may damage the lymphatic system by inhibiting lymphatic endothelial cell migration and tube formation, and a possible mechanism is the inhibition of transforming growth factor beta receptor type II (TGF-βRII) expression in lymphatic endothelial cells by miRNA-19b. Together, our findings demonstrate that atherogenic EMP may destroy lymphatic system function in atherosclerotic mice by downregulating TGF-βRII expression.
近年来，淋巴系统在动脉粥样硬化中的作用因其在免疫细胞运输、外周胆固醇清除以及炎症反应调节中的作用而受到关注。然而，在动脉粥样硬化发病机制中调节淋巴管生成和淋巴功能的机制的相关知识有限。携带循环微小RNA（miRNA）的内皮微粒已知可介导细胞间通讯，我们之前的研究表明，内皮微粒（EMP）中的miRNA-19b在循环和动脉粥样硬化血管中显著增加，并且这种内皮微粒的增加促进了动脉粥样硬化。本研究调查了致动脉粥样硬化的内皮微粒是否会影响动脉粥样硬化中淋巴系统的病理变化。我们首先验证了动脉粥样硬化小鼠中miR-19b水平的升高和淋巴系统功能的丧失。给喂食致动脉粥样硬化西方饮食的载脂蛋白E基因敲除（ApoE）小鼠静脉注射磷酸盐缓冲盐水、携带对照miRNA的内皮微粒（EMP）或内皮微粒。通过共聚焦显微镜、伊文思蓝染色和病理分析评估淋巴系统的功能和分布。结果表明，动脉粥样硬化早期存在淋巴系统功能障碍，观察到的病理变化在后期持续存在，同时伴有微小RNA-19b水平升高。在用内皮微粒全身治疗的ApoE小鼠中，淋巴系统的分布、运输功能和通透性受到显著抑制。实验表明，miRNA-19b可能通过抑制淋巴管内皮细胞迁移和管腔形成来损害淋巴系统，一种可能的机制是miRNA-19b抑制淋巴管内皮细胞中转化生长因子βⅡ型受体（TGF-βRII）的表达。总之，我们的研究结果表明，致动脉粥样硬化的内皮微粒可能通过下调TGF-βRII表达破坏动脉粥样硬化小鼠的淋巴系统功能。
