Fluid Shear Stress Regulates the Landscape of microRNAs in Endothelial Cell‐Derived Small Extracellular Vesicles and Modulates the Function of Endothelial Cells

Blood fluid shear stress (FSS) modulates endothelial function and vascular pathophysiol-ogy. 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 angio-genesis, cell migration, and vascular inflammation. OSS‐sEVs promoted tube formation, cell migra-tion, 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 mechanotrans-duction 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 estab-lishes their biological functions on a system level and provides a platform for modulating the overall phenotypic effects of sEVs.