Endothelial Microparticle-Mediated Transfer of microRNA-19b Inhibits the Function and Distribution of Lymphatic Vessels in Atherosclerotic Mice.
Endothelial Microparticle-Mediated Transfer of microRNA-19b Inhibits the Function and Distribution of Lymphatic Vessels in Atherosclerotic Mice.
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DOI：
10.3389/fphys.2022.850298
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发表时间：
2022
影响因子：
4
通讯作者：
Chen, Hong
中科院分区：
文献类型：
--
作者：
Yu, Shi-Ran;Cui, Yu-Xia;Song, Zi-Qi;Li, Su-Fang;Zhang, Chun-Ying;Song, Jun-Xian;Chen, Hong
关键词：
近年来，淋巴系统在动脉粥样硬化中的功能由于其在免疫细胞运输、从外周清除胆固醇和调节炎症反应中的作用而引起关注。然而，在动脉粥样硬化的发病机制调节淋巴管生成和淋巴功能的知识是有限的。已知携带循环microRNA（miRNA）s的内皮微粒介导细胞-细胞通讯，并且我们先前的研究表明EMPs中的miRNA-19 b（EMPmiR-19 b）在循环和动脉粥样硬化血管中显著增加，并且EMPmiR-19 b的这种增加促进动脉粥样硬化。本研究探讨了致动脉粥样硬化EMPmiR-19 b是否影响动脉粥样硬化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-19 b水平的增加和淋巴系统功能的丧失。用磷酸盐缓冲盐水、携带对照miRNA的EMP（EMP对照）或EMPmiR-19 b静脉内注射动脉粥样硬化西方饮食喂养的ApoE-/-小鼠。通过共聚焦显微镜、伊文思蓝染色和病理学分析来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，晚期病理改变持续存在，并伴有microRNA-19 b水平升高。在用EMPmiR-19 b全身处理的ApoE-/-小鼠中，淋巴系统的分布、转运功能和渗透性被显著抑制。体外实验表明，miRNA-19 b可能通过抑制淋巴管内皮细胞迁移和管腔形成而损伤淋巴系统，其机制可能是miRNA-19 b抑制淋巴管内皮细胞转化生长因子β受体II（TGF-βRII）的表达。总之，我们的研究结果表明，致动脉粥样硬化EMPmiR-19 b可能通过下调TGF-βRII表达来破坏动脉粥样硬化小鼠的淋巴系统功能。
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 (EMPmiR-19b) was significantly increased in circulation and atherosclerotic vessels, and this increase in EMPmiR-19b promoted atherosclerosis. The present study investigated whether atherogenic EMPmiR-19b 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 (EMPcontrol), or EMPmiR-19b 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 EMPmiR-19b, the distribution, transport function, and permeability of the lymphatic system were significantly inhibited. In vitro 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 EMPmiR-19b may destroy lymphatic system function in atherosclerotic mice by downregulating TGF-βRII expression.
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