Exosomal circ-1199 derived from EPCs exposed to oscillating shear stress acts as a sponge of let-7g-5p to promote endothelial-mesenchymal transition of EPCs by increasing HMGA2 expression

Abstract

AimsOur previous study showed that oscillatory shear stress (OSS) induces endothelial progenitor cells (EPCs) to undergo endothelial to mesenchymal transition (EndoMT), which may contribute to the onset and progression of atherosclerosis (AS). However, the underlying mechanisms have not been elucidated. A recent study showed that exosomes (Exos) released from EPCs played a key role in various cardiovascular diseases. The purpose of this study was to identify the role and mechanism of Exos released by EPCs exposed to OSS in EPC EndoMT. Main methodsEPCs derived from the human umbilical cord blood were cultured and characterized. The Flexcell flow STR-4000 parallel plate flow chamber system was employed to apply OSS (±3.5 dyne/cm2, 1 Hz) to EPCs for 12 h. Then, Exos were extracted from the cellular supernatant (Static-Exos) or perfusate (OSS-Exos) by exoEasy Maxi Kit. Afterward, cellular intervention, angiogenesis assays, high-throughput sequencing and online database predictions were used to identify the role and mechanism of OSS-Exos in EPC EndoMT. Key findingsOSS-Exos inhibited angiogenesis, promoted the proliferation of EPCs both in vivo and in vitro, and induced EPC EndoMT. In addition, the expression of circ-1199 in OSS-Exos was higher than that in Static-Exos. Moreover, circ-1199 induced EPC EndoMT. The dual-luciferase reporter gene assay showed that let-7g-5p was the direct target of circ-1199. Furthermore, OSS-Exos upregulated the expression of circ-1199 and then downregulated let-7g-5p, upregulating HMGA2, which activated p-Smad3/Smad3 and Snail. SignificanceOSS-Exos played an important role in the EndoMT of EPCs, which was mediated by the circ-1199/let-7g-5p/HMGA2 signaling pathway. These studies would have a high probability of revealing the mechanism of EPC EndoMT.