title: Transplantation of bone marrow‑derived endothelial progenitor cells overexpressing Delta‑like‑4 enhances functional neovascularization in ischemic myocardium.
abstract: Delta‑like‑4 (Dll‑4) prevents excess angiogenic sprouting and promotes the formation of a well‑differentiated vascular network. Therefore, transplantation of Dll‑4‑overexpressing endothelial progenitor cells (EPCs) was hypothesized to be superior to transplantation of EPCs in the treatment of ischemic heart disease. In the current study, EPCs harvested from C57BL/6 mouse bone marrow were infected in vitro with Dll‑4 (EPCDll‑4+) or Dll‑4 knockdown (EPCDll‑4‑) with recombinant lentiviral vectors and the control cells were non‑transfected or transduced with mock vectors (EPCnull). Eight‑week‑old C57BL/6 mice underwent ligation of the left anterior descending artery to establish a myocardial infarction (MI) model. The ligated animals were randomly divided into 5 groups, which, following one week, were intravenously injected with EPCs, EPCnull, EPCDll‑4+, EPCDll‑4‑ or medium. Two weeks later, echocardiographic assessment, western blotting, fluorescent microsphere and histological studies were performed. The results demonstrated that the number of mature vessels and blood flow in ischemic myocardium were increased in the EPCDll‑4+ group, but were markedly decreased in the EPCDll‑4‑ group compared with the control groups. The expression levels of Dll‑4, hairy/enhancer of split (Hes)‑related protein 1 (Hey‑1), phosphorylation of mammalian target of rapamycin (mTOR) and p70S6 kinase (p70S6K) were significantly increased in the EPCDll‑4+ group, while they were markedly decreased in the EPCDll‑4‑ group. Furthermore, for EPCDll‑4+‑treated animals, an enhanced cardiac function was observed as assessed by echocardiography. Thus, the transplantation of Dll‑4‑overexpressing EPCs stimulates neovascularization effectively, increases the blood flow to the ischemic zone and improves cardiac function. These effects may be due to the activation of Notch/Hey‑1/mTOR/p70S6K signaling pathways, which are initiated by Dll‑4.
authors.affiliation: Department of Cardiothoracic Surgery, The First People's Hospital of Nanning, Nanning, Guangxi 530022, P.R. China.
authors.forename: Hong
authors.initials: H
authors.lastname: Huang
authors.forename: Feng
authors.initials: F
authors.lastname: Huang
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Huang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001853:Bone Marrow / Q000502:physiology*; D002135:Calcium-Binding Proteins; D004452:Echocardiography; D004730:Endothelium, Vascular / Q000166:cytology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D017202:Myocardial Ischemia / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D018919:Neovascularization, Physiologic; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology*; D014407:Tumor Cells, Cultured
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C519665:DLL4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger