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.

动脉粥样硬化（AS）是一种以内皮功能障碍为特征的慢性炎症性疾病。内皮祖细胞 (EPC) 可以克服内皮功能障碍并降低 AS 风险。本研究侧重于 EPC 分泌的细胞外囊泡 (EPC-EV) 在 AS 中的作用。首先，分离和鉴定小鼠 EPCs 和小鼠主动脉内皮细胞 (MAECs)。从 EPC 中分离出 EV 并进行鉴定。EPC-EVs 与 MAECs 共培养，观察到 EVs 的内化。检测到内皮细胞中的谷胱甘肽 (GSH) 消耗、活性氧 (ROS) 产生、脂质过氧化以及铁积累和细胞死亡。使用双荧光素酶和 RIP 测定证实了 miR-199a-3p 与特异性蛋白 1 (SP1) 之间的结合关系。建立AS小鼠模型。分析miR-199a-3p表达与主动脉区斑块和血清促炎因子的关系。油红O染色检测动脉粥样硬化病变程度，ELISA检测血清炎症因子。我们的结果表明，EPC-EVs 抑制内皮细胞的细胞死亡、GSH 消耗、ROS 产生、脂质过氧化和铁积累，从而抑制内皮细胞的铁死亡。EPC-EVs 将 miR-199a-3p 转移到内皮细胞中。miR-199a-3p 靶向 SP1。在内皮细胞中沉默 miR-199a-3p 或过表达 SP1 可以逆转 EPC-EVs 对内皮细胞铁死亡的影响。体内实验证实，EPC-EVs 抑制内皮细胞的铁死亡，然后通过 miR-199a-3p/SP1 轴减轻 AS 的发生。总结一下，