Evaluation of the effects of intramyocardial injection of DNA expressing vascular endothelial growth factor (VEGF) in a myocardial infarction model in the rat--angiogenesis and angioma formation.
OBJECTIVE
The effects of direct intramyocardial injection of the plasmid encoding vascular endothelial growth factor (phVEGF165) in the border zone of myocardial infarct tissue in rat hearts were investigated.


BACKGROUND
Controversy exists concerning the ability of VEGF to induce angiogenesis and enhance coronary flow in the myocardium.


METHODS
Sprague-Dawley rats received a ligation of the left coronary artery to induce myocardial infarction (MI). At 33.1 +/- 6.5 days, the rats were injected with phVEGF165 at one location and control plasmid at a second location (500 microg DNA, n = 24) or saline (n = 16). After 33.1 +/- 5.7 days, the hearts were excised for macroscopic and histologic analysis. Regional blood flow ratios were measured in 18 rats by radioactive microspheres.


RESULTS
phVEGF165-treated sites showed macroscopic angioma-like structures at the injection site while control DNA and saline injection sites did not. By histology, 21/24 phVEGF165-treated hearts showed increased focal epicardial blood vessel density and angioma-like formation. Quantitative morphometric evaluation in 20 phVEGF165-treated hearts revealed 44.4 +/- 10.5 vascular structures per field in phVEGF165-treated hearts versus 21.4 +/- 4.7 in control DNA injection sites (p < 0.05). Regional myocardial blood flow ratios between the injection site and noninfarcted area did not demonstrate any difference between phVEGF,165-treated hearts (0.9 +/- 0.2) and saline-treated hearts (0.7 +/- 0.1).


CONCLUSIONS
Injection of DNA for VEGF in the border zone of MI in rat hearts induced angiogenesis. Angioma formation at the injection sites did not appear to contribute to regional myocardial blood flow, which may be a limitation of gene therapy for this application.
Schwarz
E R
ER
Heart Institute Research, Good Samaritan Hospital and Division of Cardiology, University of Southern California, Los Angeles 90017-2395, USA.
Speakman
M T
MT
Patterson
M
M
Hale
S S
SS
Isner
J M
JM
Kedes
L H
LH
Kloner
R A
RA
D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D016228:Endothelial Growth Factors / Q000009:adverse effects / Q000235:genetics* / Q000627:therapeutic use*; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D006338:Heart Neoplasms / Q000139:chemically induced* / Q000473:pathology; D006391:Hemangioma / Q000139:chemically induced* / Q000473:pathology; D007267:Injections; D008222:Lymphokines / Q000009:adverse effects / Q000235:genetics* / Q000627:therapeutic use*; D009203:Myocardial Infarction / Q000473:pathology / Q000628:therapy*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010957:Plasmids / Q000009:adverse effects / Q000235:genetics* / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors