Cardiac overexpression of human VEGF165 by recombinant Semliki Forest virus leads to adverse effects in pressure-induced heart failure

Abstract

Semliki Forest virus (SFV) is an efficient vector for cardiac gene delivery. The relatively short transgene expression induced by SFV seems appropriate for angiogenic gene therapy. We tested the effects of SFV expressing vascular endothelial growth factor (VEGF) on cardiac angiogenesis and heart failure in the mRen2 transgenic rat.Six-week-old mRen2 rats received SFV-VEGF or control virus (n=7 each) administered intracoronarily. Twelve days after transfection, cardiac capillary density and function were assessed. Capillary density in cardiac regions where SFV expression was highest had decreased by 20% in the SFV-VEGF-treated group. The decrease in capillary density was accompanied by impaired systolic function as illustrated by increased endsystolic volumes and a 34% decrease in cardiac output.We conclude that the time frame of SFV expression is sufficient to induce structural alterations, but that VEGF in mRen2 transgenic rats did not elicit the expected angiogenic effect. Rather, capillary density was decreased and subsequently cardiac function was impaired. This paradoxical finding is possibly related to the pathophysiology associated with this model and warrants caution if one is to pursue VEGF-mediated, angiogenic therapy before proceeding to a clinical setting. (Neth Heart J 2007;15:335-41.).