Notch pathway activation mediated the senescence of endothelial progenitor cells in hypercholesterolemic mice.

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.