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J Am Coll Cardiol, 2000; 35:1323-1330
© 2000 by the American College of Cardiology Foundation
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EXPERIMENTAL STUDIES

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

Ernst R. Schwarz, MD* {dagger}, Mark T. Speakman, MD* {dagger}, Mike Patterson, PhD*, Sharon S. Hale, BS*, Jeffrey M. Isner, MD{ddagger}, Laurence H. Kedes, MD§ and Robert A. Kloner, MD, PhD* {dagger}

* Heart Institute Research, Good Samaritan Hospital, Los Angeles, California, USA
{dagger} Division of Cardiology, University of Southern California, Los Angeles, California, USA
{ddagger} Division of Cardiovascular Research, St. Elisabeth’s Medical Center and Tufts University School of Medicine, Boston, Massachusetts, USA
§ Department of Biochemistry and Molecular Biology, Department of Medicine, University of Southern California, Los Angeles, California, USA

Manuscript received February 4, 1999; revised manuscript received November 5, 1999, accepted December 15, 1999.

Reprint requests and correspondence: Dr. Robert A. Kloner, Heart Institute, Good Samaritan Hospital & Division of Cardiology, University of Southern California, 1225 Wilshire Boulevard, Los Angeles, California 90017-2395
RKloner{at}goodsam.org

OBJECTIVES

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 µg 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 phVEGF165-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.

Abbreviations and Acronyms
  CMV = cytomegalovirus
  DNA = deoxyribonucleic acid
  ECG = electrocardiogram
  H + E = hematoxylin and eosin
  MI = myocardial infarction
  VEGF = vascular endothelial growth factor




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