Arteriogenesis Induced by Intramyocardial Vascular Endothelial Growth Factor 165 Gene Transfer in Chronically Ischemic Pigs

Abstract

Exogenous vascular endothelial growth factor (VEGF) improves tissue perfusion in large animals and humans with chronic myocardial ischemia. Because tissue perfusion is mainly dependent on the arteriolar tree, we hypothesized that the neovascularizing effect of VEGF should include arteriogenesis, an effect not as yet described in large mammalian models of myocardial ischemia. In the present study we investigated the effect of intramyocardial plasmid-mediated human VEGF(165) gene transfer (pVEGF(165)) on the proliferation of vessels with smooth muscle in a pig model of myocardial ischemia. In addition, we assessed the effect of treatment on capillary growth, myocardial perfusion, myocardial function and collateralization. Three weeks after positioning of an Ameroid constrictor (Research Instruments SW, Escondido, CA) in the left circumflex artery, pigs underwent basal perfusion (single-photon emission computed tomography [SPECT] with (99m)Tc-sestamibi) and regional function (echocardiography) studies at rest and under dobutamine stress, and were then randomly assigned to receive transepicardial injection of pVEGF(165) 3.8 mg (n = 8) or placebo (empty plasmid, n = 8). All experimental steps and data analysis were done in a blinded fashion. Five weeks later, pVEGF(165)-treated pigs showed a significantly higher density of small (8-50 microm in diameter) vessels with smooth muscle, higher density of capillaries, and improved myocardial perfusion. These results indicate an arteriogenic effect of VEGF in a large mammalian model of myocardial ischemia and encourage the use of VEGF to promote arteriolar growth in patients with severe coronary artery disease.

Polymeric gene delivery of ischemia-inducible VEGF significantly attenuates infarct size and apoptosis following myocardial infarct

“…In addition to these two mechanisms, VEGF gene therapy has previously been shown to (1) promote arteriogenesis and (2) have a mitogenic effect on adult cardiomyocytes in large animal models of myocardial ischemia and infarction. [17][18][19] Both of these previously described mechanisms most likely also contribute to the significant decrease in myocardial infarct size seen in this study.…”

Intrathecal transplantation of human neural stem cells overexpressing VEGF provide behavioral improvement, disease onset delay and survival extension in transgenic ALS mice

“…[16][17][18][19] VEGF is one of such growth factors that can be used in combination with transplanted stem cells to improve therapeutic efficiency of cellular transplantation. VEGF is an angiogenetic growth factor acting as a potent mitogen and survival factor for endothelial cells, 20,21 smooth muscle cells, 22,23 hepatocytes 24 and cardiomyocytes, 25,26 and also known for neuroprotective effect against brain injury. 27,28 Several recent studies have also shown that VEGF promoted cell survival pathways and blocked cell death in the ALS animal model.…”

Angiopoietin-1 promotes functional neovascularization that relieves ischemia by improving regional reperfusion in a swine chronic myocardial ischemia model

“…Successful therapeutic angiogenesis has been reported with vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) in ischemic animal models [1,2]. Early clinical trials in a small number of myocardial ischemic patients have been encouraging [3][4][5][6].…”