Hyperlipidemia is an important factor in the induction of cardiovascular diseases. However, the molecular mechanisms underlying the vascular injury involved in hyperlipidemia remains unclear. This study aimed to investigate the Notch pathway of endothelial progenitor cells (EPCs) in reendothelialization after vascular injury and to explore the involvement of Notch pathway in the senescence of EPCs. Our results demonstrated that high-fat diet (HFD) treatment inhibited reendothelialization after vascular injury in the mice model. In vitro studies showed that 7-ketocholesterol (7-keto) stimulation induced senescence in the isolated EPCs from mice. In addition, 7-keto markedly upregulated the protein expression of Notch1 and Delta-like ligand 4 and induced the transport of notch intracellular domain (NICD) to the nucleus. Mechanistically, treatment with NICD inhibitor reduced the senescence of the EPCs stimulated by cholesterol. In summary, our results showed that HFD treatment caused the disruption of reendothelialization after vascular injury in the mouse model. In vitro studies indicated that 7-keto-induced senescence of EPCs was at least via the activation of the Notch1 pathway. Mechanistic data suggested that 7-keto may activate the Notch1 pathway by regulating the generation and transport of NICD to the nucleus. Future investigations are warranted to confirm the role of Notch1 in the dysfunction of EPCs during obesity.

高脂血症是诱发心血管疾病的重要因素。然而，高脂血症所涉及的血管损伤的分子机制仍不清楚。本研究旨在探讨血管损伤后内皮祖细胞（EPCs）在再内皮化过程中的Notch通路，探讨Notch通路在EPCs衰老过程中的作用。我们的结果表明，高脂肪饮食 (HFD) 治疗抑制了小鼠模型血管损伤后的再内皮化。体外研究表明，7-酮胆固醇（7-酮）刺激诱导小鼠分离的 EPC 衰老。此外，7-keto 显着上调 Notch1 和 Delta 样配体 4 的蛋白质表达，并诱导缺口胞内结构域 (NICD) 向细胞核的转运。从机制上讲，用 NICD 抑制剂治疗减少了胆固醇刺激的 EPC 的衰老。总之，我们的结果表明，HFD 治疗导致小鼠模型血管损伤后再内皮化的中断。体外研究表明，7-酮诱导的 EPC 衰老至少是通过 Notch1 通路的激活。机制数据表明，7-keto 可能通过调节 NICD 的产生和转运到细胞核来激活 Notch1 通路。未来的研究有必要确认 Notch1 在肥胖期间 EPC 功能障碍中的作用。体外研究表明，7-酮诱导的 EPC 衰老至少是通过 Notch1 通路的激活。机制数据表明，7-keto 可能通过调节 NICD 的产生和转运到细胞核来激活 Notch1 通路。未来的研究有必要确认 Notch1 在肥胖期间 EPC 功能障碍中的作用。体外研究表明，7-酮诱导的 EPC 衰老至少是通过 Notch1 通路的激活。机制数据表明，7-keto 可能通过调节 NICD 的产生和转运到细胞核来激活 Notch1 通路。未来的研究有必要确认 Notch1 在肥胖期间 EPC 功能障碍中的作用。