Enhanced myocardial angiogenesis by gene transfer with transplanted cells.
BACKGROUND The combination of myocardial cell transplantation and angiogenic gene transfer may improve postinfarction left ventricular (LV) perfusion. We evaluated the angiogenic effect of heart cells transfected with vascular endothelial growth factor (VEGF) and transplanted into a myocardial scar.


RESULTS
Donor rat heart cells were transfected with plasmids encoding VEGF(165) and green fluorescence protein. Syngeneic adult rats underwent LV cryoinjury to create a transmural scar. Three weeks later, 4x10(6) transfected heart cells (n=14), untransfected heart cells (n=13), or culture medium (n=16) were transplanted into the center of the scar. After 5 weeks, LV function, quantitative histology, and regional blood flow were evaluated. Plates of heart cells transfected with VEGF(165) produced 6.1 times more intracellular VEGF than nontransfected cells. Capillary density (mean+/-SEM) per high-power field in the center of the myocardial scar was 1.1+/-0.02 in control rats, 3.9+/-0.11 in untransfected rats, and 6.3+/-0.11 in transfected rats (P=0.0002). Capillary density in the border zone around the scar was 1.9+/-0.03 in control rats, 6.4+/-0.10 in untransfected rats, and 8.7+/-0.16 in transfected rats (P=0.004). Regional blood flow within the scar was 8.8+/-0.8% of normalized flow in control hearts, 10.4+/-0.7% in hearts transplanted with untransfected cells, but 17.6+/-1.2% in hearts transplanted with transfected cells (P=0.03 versus control, P=0.07 versus nontransfected). There was no difference in LV function attributable to transplantation with transfected cells at the time point studied.


CONCLUSIONS
Transplantation of heart cells transfected with VEGF induced greater angiogenesis than transplantation of unmodified cells. Combined gene transfer and cell transplantation strategies may improve postinfarction LV perfusion and function.
Yau
T M
TM
Division of Cardiovascular Surgery, Toronto General Hospital, University Health Network, Department of Surgery, University of Toronto, Toronto, Ontario, Canada. terry.yau@utoronto.ca
Fung
K
K
Weisel
R D
RD
Fujii
T
T
Mickle
D A
DA
Li
R K
RK
D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects / Q000235:genetics; D002452:Cell Count; D017690:Cell Transplantation; D002478:Cells, Cultured; D003326:Coronary Circulation / Q000187:drug effects / Q000235:genetics; D016228:Endothelial Growth Factors / Q000096:biosynthesis / Q000235:genetics* / Q000494:pharmacology; D015870:Gene Expression; D022761:Gene Transfer, Horizontal; D017930:Genes, Reporter / Q000235:genetics; D049452:Green Fluorescent Proteins; D008164:Luminescent Proteins / Q000235:genetics; D008222:Lymphokines / Q000096:biosynthesis / Q000235:genetics* / Q000494:pharmacology; D008297:Male; D009204:Myocardial Revascularization / Q000379:methods*; D009206:Myocardium / Q000166:cytology* / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics*; D051381:Rats; D011917:Rats, Inbred Lew; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016277:Ventricular Function, Left
D016228:Endothelial Growth Factors; D008164:Luminescent Proteins; D008222:Lymphokines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D049452:Green Fluorescent Proteins