Fluid Shear Stress Regulates the Landscape of microRNAs in Endothelial Cell-Derived Small Extracellular Vesicles and Modulates the Function of Endothelial Cells.
Fluid Shear Stress Regulates the Landscape of microRNAs in Endothelial Cell-Derived Small Extracellular Vesicles and Modulates the Function of Endothelial Cells.
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DOI：
10.3390/ijms23031314
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发表时间：
2022-01-24
影响因子：
5.6
通讯作者：
Kwon K
中科院分区：
文献类型：
--
作者：
Chung J;Kim KH;Yu N;An SH;Lee S;Kwon K
血液剪切应力（FSS）调节内皮功能和血管病理生理学。外泌体等小细胞外囊泡 (sEV) 是细胞间通讯的有效介质，其内容物反映了细胞应激。在这里，我们探索了内皮细胞（EC）衍生的 sEV（EC-sEV）在动脉粥样硬化保护层流剪切应力（LSS）和动脉粥样硬化易发性低振荡剪切应力（OSS）下的 miRNA 图谱，并进行了网络分析，以确定 sEV 的 miRNA 调节的主要生物过程。 EC-sEVs是从暴露于动脉粥样硬化LSS（20达因/cm2）和易发生动脉粥样硬化的OSS（±5达因/cm2）的人脐静脉内皮细胞的培养基中收集的。我们探索了 FSS 诱导的 EC-sEV（LSS-sEV 和 OSS-sEV）中的 miRNA 图谱，并进行了网络分析，以确定 sEV 的 miRNA 调节的主要生物过程。在部分颈动脉结扎的小鼠模型中进行了体内研究。 sEV 的 miRNA 靶向基因富集用于内皮激活，例如血管生成、细胞迁移和血管炎症。 OSS-sEV 促进管形成、细胞迁移、单核细胞粘附和细胞凋亡，并上调刺激这些生物过程的蛋白质表达。 FSS 诱导的 EC-sEV 对内皮机械转导信号传导的影响与 FSS 直接刺激相同。体内研究表明，LSS-sEVs 降低了促炎基因的表达，而 OSS-sEVs 则具有相反的作用。这项研究了解了受不同 FSS 模式调节的 EC 外泌体 miRNA 的情况，在系统水平上建立了它们的生物学功能，并为调节 sEV 的整体表型效应提供了一个平台。
Blood fluid shear stress (FSS) modulates endothelial function and vascular pathophysiology. The small extracellular vesicles (sEVs) such as exosomes are potent mediators of intercellular communication, and their contents reflect cellular stress. Here, we explored the miRNA profiles in endothelial cells (EC)-derived sEVs (EC-sEVs) under atheroprotective laminar shear stress (LSS) and atheroprone low-oscillatory shear stress (OSS) and conducted a network analysis to identify the main biological processes modulated by sEVs’ miRNAs. The EC-sEVs were collected from culture media of human umbilical vein endothelial cells exposed to atheroprotective LSS (20 dyne/cm2) and atheroprone OSS (±5 dyne/cm2). We explored the miRNA profiles in FSS-induced EC-sEVs (LSS-sEVs and OSS-sEVs) and conducted a network analysis to identify the main biological processes modulated by sEVs’ miRNAs. In vivo studies were performed in a mouse model of partial carotid ligation. The sEVs’ miRNAs-targeted genes were enriched for endothelial activation such as angiogenesis, cell migration, and vascular inflammation. OSS-sEVs promoted tube formation, cell migration, monocyte adhesion, and apoptosis, and upregulated the expression of proteins that stimulate these biological processes. FSS-induced EC-sEVs had the same effects on endothelial mechanotransduction signaling as direct stimulation by FSS. In vivo studies showed that LSS-sEVs reduced the expression of pro-inflammatory genes, whereas OSS-sEVs had the opposite effect. Understanding the landscape of EC-exosomal miRNAs regulated by differential FSS patterns, this research establishes their biological functions on a system level and provides a platform for modulating the overall phenotypic effects of sEVs.
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