Arteriogenesis induced by vascular endothelial growth factor 165 gene transfer in chronically ischemic pigs

pp 23-30

Abstract

Vascular endothelial growth factor (VEGF), an endothelial cell-specific angiogen, improves myocardial perfusion in large animals and humans with chronic myocardial ischemia. Since tissue perfusion is mainly dependent upon the arteriolar tree and VEGF receptors have been shown to be present in vascular smooth muscle cells, VEGF administration should also promote arteriogenesis. We thus investigated the hypothetic arteriogenic effect of intramyocardial administration of a new plasmid encoding for recombinant human VEGF (pCMVrhVEGF165), developed and produced in Argentina, in a pig model of chronic myocardial ischemia. Three weeks after positioning of an Ameroid constrictor in the left circumflex coronary artery, 16 pigs underwent myocardial function studies (echocardiography) at rest and under pharmacological challenge (dobutamine), and were then randomized into a treated group (n=8) that received 10 direct intramyocardial injections of pCMVrh VEGF 165 (3.8 mg) and a placebo group (n=8) that received plasmid devoid of gene. Five weeks later, function studies were repeated , a coronary angiography was performed and the heart and remote tissues were removed for histological analysis. All experimental steps were done in a blinded fashion. Treated pigs showed, as compared with placebo pigs, significantly higher length density ( 2 .4±0.4 vs. 1.3±0.3 mm/mm3 ; p<0,02) and numerical density (1±0,1 vs. 0,6±0,1 mm-2 , p<0,02) of small ( < 50 mm in diameter) vessels with smooth muscle layer (immunohistochemistry). No evidence of undesired neovascular proliferation was found in remote tissues. We conclude that direct intramyocardial injection of pCMVrhVEGF165 in chronically ischemic pigs is safe and induces arteriogenesis.