title: Enhanced angiogenesis with multimodal cell-based gene therapy.
abstract: BACKGROUND
  We evaluated the synergism of transient vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) overexpression on angiogenesis and left ventricular (LV) function after bone marrow cell (BMC) transplantation, to determine the potential of multimodal cell-based gene therapy for myocardial repair.
  
  
  METHODS
  Female Lewis rats underwent coronary ligation 3 weeks before transplantation with male donor BMC, BMC transfected with VEGF (BMC+VEGF), bFGF (BMC+bFGF), VEGF and bFGF (BMC+VEGF+bFGF), or medium (control) (n = 3 each group at 3 days, 1 week and 2 weeks; n = 6 each group at 4 weeks; n = 75 total). Three days, 1 week, 2 weeks, and 4 weeks after transplantation, transgene expression was quantitated by real-time polymerase chain reaction, angiogenesis by quantitative histology, and LV function by echocardiography. At 4 weeks, regional perfusion was quantitated with microspheres.
  
  
  RESULTS
  The VEGF and bFGF were expressed transiently over 4 weeks. At 1 week, VEGF expression was greatest in BMC+VEGF and BMC+VEGF+bFGF hearts (p < 0.05), while bFGF expression was greatest in BMC+bFGF and BMC+VEGF+bFGF rats (p < 0.05). Regional perfusion and vascular densities in the scar were lowest in control, intermediate in BMC, BMC+VEGF, BMC+bFGF, and greatest in BMC+VEGF+bFGF (p < 0.05). Four weeks after transplantation, LV ejection fraction was lowest in control, intermediate in BMC, BMC+VEGF and BMC+bFGF, and greatest in BMC+VEGF+bFGF (p < 0.05).
  
  
  CONCLUSIONS
  The VEGF and bFGF transgenes were expressed transiently and exerted a powerful synergism on the angiogenic effect of cell transplantation, but did not normalize perfusion or function. The future of cell transplantation may lie in multimodal cell-based gene therapy, in combination with other novel therapies.
authors.affiliation: Division of Cardiovascular Surgery, Toronto General Hospital, Ontario, Canada. terry.yau@uhn.on.ca
authors.forename: Terrence M
authors.initials: TM
authors.lastname: Yau
authors.forename: Christopher
authors.initials: C
authors.lastname: Kim
authors.forename: Guangming
authors.initials: G
authors.lastname: Li
authors.forename: Yaoguang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Shafie
authors.initials: S
authors.lastname: Fazel
authors.forename: Dan
authors.initials: D
authors.lastname: Spiegelstein
authors.forename: Richard D
authors.initials: RD
authors.lastname: Weisel
authors.forename: Ren-Ke
authors.initials: RK
authors.lastname: Li
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D016026:Bone Marrow Transplantation; D003326:Coronary Circulation; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D015316:Genetic Therapy; D008297:Male; D009203:Myocardial Infarction / Q000503:physiopathology / Q000628:therapy*; D018919:Neovascularization, Physiologic; D011184:Postoperative Period; D051381:Rats; D011917:Rats, Inbred Lew; D014162:Transfection; D019076:Transgenes; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism; D016277:Ventricular Function, Left
chemical_list: D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2