HuMSC-EVs Protect Endothelial Cells Against Hypoxia/Reoxygenation Injury by Inhibiting the Pannexin 1/p38-MAPK Pathway.

Vascular endothelial cell dysfunction plays an important role in myocardial ischemia-reperfusion (I/R) injury, and pannexin 1 (Panx1), an ATP-permeable channel, is closely associated with the pathophysiological processes of I/R injury. The purpose of this study was to investigate the protective effects of human umbilical cord mesenchymal stromal cell-derived extracellular vesicles (HuMSC-EVs) and the underlying mechanism in a model of I/R injury. For the cellular model of I/R injury, human umbilical vein endothelial cells (HuVECs) were exposed to hypoxia/reoxygenation (H/R) conditions. The model cells were then treated with HuMSC-EVs, and the effects on cell survival and specific signaling activities were observed. The results showed that after H/R exposure, Panx1 expression and other markers of cellular damage were increased in HuVECs. However, treatment with HuMSC-EVs inhibited the H/R-induced increase in Panx1 expression and improved HuVEC survival. Mechanistically, HuMSC-EVs were found to inhibit the p38 mitogen-activated protein kinase (MAPK)-dependent apoptosis pathway, as evidenced by increased Bcl2 expression and reductions in p38 MAPK phosphorylation, Bax expression, and cleaved-caspase 3 expression. Together our data suggest that HuMSC-EVs alleviate H/R-induced apoptosis among HuVECs by inhibiting activity of the Panx1/p38-MAPK-dependent apoptosis pathway.