Effect of endothelial progenitor cell-derived extracellular vesicles on endothelial cell ferroptosis and atherosclerotic vascular endothelial injury

Abstract

Atherosclerosis (AS) is a chronic inflammatory disorder characterized by endothelial dysfunction. Endothelial progenitor cells (EPCs) can overcome endothelial dysfunction and reduce AS risk. This study focused on the role of EPC-secreted extracellular vesicles (EPC-EVs) in AS. First, mouse EPCs and mouse aortic endothelial cells (MAECs) were isolated and identified. EVs were isolated from EPCs and identified. EPC-EVs were co-cultured with MAECs and the internalization of EVs was observed. Glutathione (GSH) consumption, reactive oxygen species (ROS) production, lipid peroxidation, and iron accumulation and cell death in endothelial cells were detected. The binding relationship between miR-199a-3p and specificity protein 1 (SP1) was confirmed using dual-luciferase and RIP assays. The mouse model of AS was established. The relationships between miR-199a-3p expression and aortic area plaque and serum pro-inflammatory factor were analyzed. The degree of atherosclerotic lesion was detected using oil red O staining and the serum inflammatory factors were detected using ELISA. Our results elicited that EPC-EVs inhibited cell death, GSH consumption, ROS production, lipid peroxidation, and iron accumulation in endothelial cells, thereby suppressing ferroptosis of endothelial cells. EPC-EVs transferred miR-199a-3p into endothelial cells. miR-199a-3p targeted SP1. Silencing miR-199a-3p or overexpression of SP1 in endothelial cells reversed the effect of EPC-EVs on ferroptosis of endothelial cells. In vivo experiments confirmed that EPC-EVs inhibited ferroptosis of endothelial cells and then alleviated the occurrence of AS via the miR-199a-3p/SP1 axis. To conclude, EPC-EVs transferred miR-199a-3p to inhibit SP1, thus repressing ferroptosis of endothelial cells and retarding the occurrence of AS.

Extracellular Vesicles as Drivers of Immunoinflammation in Atherothrombosis

“…Along the same line, Jansen et al showed that eMV uptake in ECs via annexin I/PS receptor-p38 signaling protects against apoptosis [ 75 ]. Li et al have demonstrated that endothelial progenitor cell (EPC)-derived EVs inhibit ferroptosis and alleviate atherosclerosis vascular injury via the miR-199a-3p/specificity protein 1 axis [ 76 ]. Of interest, EVs in basal conditions or from healthy subjects do not show deleterious effects to the vascular wall [ 77 , 78 ], highlighting that the impact of EVs in vivo is cell source- and context-dependent [ 79 , 80 , 81 , 82 , 83 ].…”

Elabela promotes the retinal angiogenesis by inhibiting ferroptosis during the vaso‐obliteration phase in mouse oxygen‐induced retinopathy model

“…In past studies, ferroptosis occurred in ECs under oxidative stress-mediated injuries, such as in coronary artery and pulmonary microvascular endothelial cells. [26][27][28] Thus, the hallmark of ferroptosis was investigated in RMECs, and our results found an overwhelming accumulation of Fe 2+ , ROS, and lipid peroxidation in the H 2 O 2 treatment cells. Previous studies have provided evidence that ROS is highly involved in ROP.…”

“…Further exploration of underlying mechanisms is desirable. In past studies, ferroptosis occurred in ECs under oxidative stress‐mediated injuries, such as in coronary artery and pulmonary microvascular endothelial cells 26–28 …”

Comprehensive insight into endothelial progenitor cell-derived extracellular vesicles as a promising candidate for disease treatment

“…Atherosclerosis is a chronic inflammatory disorder characterized by endothelial dysfunction. Li et al proved that EPC-EVs can suppress the ferroptosis of ECs and mitigate the occurrence of atherosclerosis by transferring miR-199a-3p to inhibit specificity protein 1 (SP1) [ 146 ].…”