title: Synergistic effect of bone marrow mobilization and vascular endothelial growth factor-2 gene therapy in myocardial ischemia.
abstract: BACKGROUND
  We performed a series of investigations to test the hypothesis that combining angiogenic gene therapy and cytokine (CK)-induced endothelial progenitor cell mobilization would be superior to either strategy alone for treatment of chronic myocardial ischemia.
  
  
  RESULTS
  A swine model of chronic myocardial ischemia and a murine model of acute myocardial infarction were used in this study. In both models, animals were randomly assigned to 1 of 4 treatment groups: Combo group, intramyocardial vascular endothelial growth factor (VEGF)-2 gene transfer plus subcutaneous injection of CKs; VEGF-2, VEGF-2 gene transfer plus saline subcutaneously injected; CK, empty vector transfer plus CKs; and control, empty vector plus subcutaneous saline. Acute myocardial infarction was also induced in wild-type mice 4 weeks after bone marrow transplantation from enhanced green fluorescent protein transgenic mice to permit observation of bone marrow-derived cells in the myocardium after acute myocardial infarction. In chronic myocardial ischemia, combination therapy resulted in superior improvement in all indexes of perfusion and function compared with all other treatment groups. In the bone marrow transplant mice, double immunofluorescent staining revealed that the combination of CK-induced mobilization and local VEGF-2 gene transfer resulted in a significant increase in the number of bone marrow-derived cells incorporating into the neovasculature, indicating that recruitment and/or retention of bone marrow-derived progenitors was enhanced by mobilization and that local VEGF-2 gene transfer can provide signals for recruitment or incorporation of circulating progenitor cells.
  
  
  CONCLUSIONS
  Mobilization of endothelial progenitor cells with cytokines potentiates VEGF-2 gene therapy for myocardial ischemia and enhances bone marrow cell incorporation into ischemic myocardium.
authors.affiliation: Division of Cardiovascular Research, St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Mass 02135, USA.
authors.forename: Atsuhiko
authors.initials: A
authors.lastname: Kawamoto
authors.forename: Toshinori
authors.initials: T
authors.lastname: Murayama
authors.forename: Kengo
authors.initials: K
authors.lastname: Kusano
authors.forename: Masaaki
authors.initials: M
authors.lastname: Ii
authors.forename: Tengiz
authors.initials: T
authors.lastname: Tkebuchava
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shintani
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iwakura
authors.forename: Ingrid
authors.initials: I
authors.lastname: Johnson
authors.forename: Patrick
authors.initials: P
authors.lastname: von Samson
authors.forename: Allison
authors.initials: A
authors.lastname: Hanley
authors.forename: Mary
authors.initials: M
authors.lastname: Gavin
authors.forename: Cindy
authors.initials: C
authors.lastname: Curry
authors.forename: Marcy
authors.initials: M
authors.lastname: Silver
authors.forename: Hong
authors.initials: H
authors.lastname: Ma
authors.forename: Marianne
authors.initials: M
authors.lastname: Kearney
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Losordo
mesh_terms: D000818:Animals; D003131:Combined Modality Therapy; D017023:Coronary Angiography; D022062:Electrophysiologic Techniques, Cardiac; D017930:Genes, Reporter; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000627:therapeutic use; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use*; D049452:Green Fluorescent Proteins / Q000032:analysis / Q000235:genetics; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015552:Injections, Intralesional; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000628:therapy*; D017202:Myocardial Ischemia / Q000000981:diagnostic imaging / Q000473:pathology / Q000628:therapy*; D011828:Radiation Chimera; D011897:Random Allocation; D011993:Recombinant Fusion Proteins / Q000502:physiology; D011994:Recombinant Proteins / Q000627:therapeutic use*; D019089:Stem Cell Factor / Q000627:therapeutic use*; D034421:Sus scrofa; D014463:Ultrasonography; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000502:physiology*; D018487:Ventricular Dysfunction, Left / Q000000981:diagnostic imaging / Q000209:etiology
chemical_list: D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D019089:Stem Cell Factor; D042461:Vascular Endothelial Growth Factor A; D016179:Granulocyte Colony-Stimulating Factor; D049452:Green Fluorescent Proteins