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

Alberto Crottogini, Verónica Martínez, Andrea De Lorenzi, Juan Telayna, Aníbal Mele, José L. Fernández, Laura Marangunich, Marcelo Criscuolo, Maurizio C. Capogrossi, Rubén Laguens, Patricia Cabeza Meckert, Gustavo Vera Janavel, Elena Lascano, Jorge Negroni, Héctor Del Valle, Eduardo Dulbecco, Pablo Werba, Luis Cuniberti

Research output: Contribution to journalArticle

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 VEGF165 gene transfer (pVEGF165) 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 99mTc-sestamibi) and regional function (echocardiography) studies at rest and under dobutamine stress, and were then randomly assigned to receive transepicardial injection of pVEGF165 3.8 mg (n = 8) or placebo (empty plasmid, n = 8). All experimental steps and data analysis were clone in a blinded fashion. Five weeks later, pVEGF165-treated pigs showed a significantly higher density of small (8-50 μm 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.

Original languageEnglish
Pages (from-to)1307-1318
Number of pages12
JournalHuman Gene Therapy
Volume14
Issue number14
DOIs
Publication statusPublished - Sep 20 2003

ASJC Scopus subject areas

  • Genetics

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    Crottogini, A., Martínez, V., De Lorenzi, A., Telayna, J., Mele, A., Fernández, J. L., Marangunich, L., Criscuolo, M., Capogrossi, M. C., Laguens, R., Meckert, P. C., Vera Janavel, G., Lascano, E., Negroni, J., Del Valle, H., Dulbecco, E., Werba, P., & Cuniberti, L. (2003). Arteriogenesis induced by intramyocardial vascular endothelial growth factor 165 gene transfer in chronically ischemic pigs. Human Gene Therapy, 14(14), 1307-1318. https://doi.org/10.1089/104303403322319390