Mounting evidence indicates that the function of members of the
vascular endothelial growth factor (
VEGF) family extends beyond blood vessel formation. Here, we show that the prolonged intramyocardial expression of VEGF-A(165) and
VEGF-B(167) on adeno-associated virus-mediated gene delivery determined a marked improvement in cardiac function after
myocardial infarction in rats, by promoting cardiac contractility, preserving viable cardiac tissue, and preventing remodeling of the left ventricle (LV) over time. Consistent with this functional outcome, animals treated with both factors showed diminished
fibrosis and increased contractile myocardium, which were more pronounced after expression of the selective
VEGF receptor-1 (VEGFR-1)
ligand VEGF-B, in the absence of significant induction of angiogenesis. We found that cardiomyocytes expressed
VEGFR-1,
VEGFR-2, and
neuropilin-1 and that, in particular,
VEGFR-1 was specifically up-regulated in
hypoxia and on exposure to oxidative stress.
VEGF-B exerted powerful antiapoptotic effect in both cultured cardiomyocytes and after
myocardial infarction in vivo. Finally,
VEGFR-1 activation by
VEGF-B was found to elicit a peculiar gene expression profile proper of the compensatory, hypertrophic response, consisting in activation of alphaMHC and repression of betaMHC and skeletal
alpha-actin, and an increase in SERCA2a, RYR, PGC1alpha, and cardiac
natriuretic peptide transcripts, both in cultured cardiomyocytes and in infarcted hearts. The finding that
VEGFR-1 activation by
VEGF-B prevents loss of cardiac mass and promotes maintenance of cardiac contractility over time has obvious therapeutic implications.