Intramyocardial injection of DNA encoding vascular endothelial growth factor in a myocardial infarction model

In a previous study, we observed that one injection of 500 mug of DNA for the plasmid encoding for vascular endothelial growth factor (ph VEGF(165)) into one site in a rat myocardial infarction model resulted in neovascularization confined to angiomatous structures that did not contribute to regional myocardial blood flow. The purpose of the present study was to determine whether a lower dose (125 mug DNA), which is the same as that being used in some clinical trials, injected into four separate sites could enhance collateral flow and vascularity to the ischemic bed without inducing angiomas. Rats received injections of 125 mug DNA of the plasmid encoding phVEGF(165) or control DNA at four separate sites within the anterior free wall of the left ventricle (LV) supplied by the left coronary artery. The left coronary artery was ligated and hearts analyzed at 4 weeks. In vitro studies confirmed that the phVEGF(165) used was capable of producing VEGF polypeptide in mammalian cells. The infarct size (percentage of endocardial circumference that infarcted) was similar in controls (42 +/-6%) and treated hearts (39 +/-7%); the LV cavity area did not differ between groups. The number of vascular structures per high-power field within the infarct scar was 10.50 +/-0.68 in controls and 10.00 +/-0.85 in phVEGF(165)-treated rats. Relative regional myocardial blood flow determined by radioactive microspheres and expressed as a ratio of radioactive counts within the scar divided by radioactive counts in the noninfarcted ventricular septum was similar in control (0.74 +/-0.25) and treated hearts (0.88 +/-0.30) (p = not significant). No angiomatous structures were observed. Injections of 125 mug of DNA of phVEGF(165) into myocardium to become ischemic had no effect on infarct size or LV cavity size. Unlike higher doses of 500 mug of DNA, it did not cause gross angiomatous structures; however, it failed to improve neovascularization or regional myocardial blood flow in this rodent model of acute myocardial infarction.