Enhanced angiogenesis with multimodal cell-based gene therapy.
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.
Yau
Terrence M
TM
Division of Cardiovascular Surgery, Toronto General Hospital, Ontario, Canada. terry.yau@uhn.on.ca
Kim
Christopher
C
Li
Guangming
G
Zhang
Yaoguang
Y
Fazel
Shafie
S
Spiegelstein
Dan
D
Weisel
Richard D
RD
Li
Ren-Ke
RK
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
D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2