Journal
FASEB JOURNAL
Volume 24, Issue 5, Pages 1467-1478Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.09-143180
Keywords
apoptosis; adeno-associated virus; angiogenesis; gene therapy; gene expression
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Funding
- Fondazione CR Trieste, Trieste, Italy
- Regione Friuli Venezia Giulia, Italy
- World Anti-Doping Agency (WADA), Montreal, Canada
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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-A165 and VEGF-B167 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 alpha MHC and repression of beta MHC and skeletal alpha-actin, and an increase in SERCA2a, RYR, PGC1 alpha, 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.-Zentilin, L., Puligadda, U., Lionetti, V., Zacchigna, S., Collesi, C., Pattarini, L., Ruozi, G., Camporesi, S., Sinagra, G., Pepe, M., Recchia, F. A., Giacca, M. Cardiomyocyte VEGFR-1 activation by VEGF-B induces compensatory hypertrophy and preserves cardiac function after myocardial infarction. FASEB J. 24, 1467-1478 (2010). www.fasebj.org
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