Vascular endothelial growth factor B attenuates a set of pathological alterations in the aged heart

Nivethitha Manickam (Frankfurt am Main)1, I. Sultan (Helsinki)2, J. Panthel (Frankfurt am Main)1, H. Kujundzic (Frankfurt am Main)1, A. Fischer (Frankfurt am Main)1, K. Schmitz (Frankfurt am Main)1, W. Abplanalp (Frankfurt am Main)1, K. Alitalo (Helsinki)2, J. Wagner (Frankfurt am Main)1, S. Dimmeler (Frankfurt am Main)1

1Universitätsklinikum Frankfurt Zentrum für Molekulare Medizin, Institut für Kardiovaskuläre Regeneration Frankfurt am Main, Deutschland; 2Wihuri Research Institute Biomedicum Helsinki Helsinki, Deutschland


VEGF ligands belongs to cysteine knot family of secreted growth factors and signal via cognate tyrosine kinase receptors. Out of the five VEGF ligands, VEGFA and VEGFB involved in blood vessel development and maintenance, angiogenesis in retina, ischemic tissues and wound healing. Promoting VEGFA signaling in aged mice has been shown to delay various aging phenotypes and extend the survival of aged mice (Grunewald et al, 2021). Although there is profound knowledge on functions of VEGFA, VEGFB in angiogenesis and cell survival, these have not been investigated in the context of cardiac aging. Our bulk RNA sequencing of various cell types of aged mouse hearts revealed significant downregulation of Vegfb in endothelial cells. VEGFB was also downregulated in cardiomyocytes of aortic valve stenosis patients. Hence, we investigated whether gene therapy with Vegfb can revert age-dependent cardiac pathologies. We overexpressed Vegfb186, the soluble VEGFB isoform via AAV9 vector transduction into 18-month-old C57Bl/6J male mice. Vegfb186 treatment delayed age-related diastolic dysfunction and decreased cardiac fibrosis (0.26±0.08-fold, p<0.05). We further found a tendency towards reduced senescence (0.14±0.15 fold) as shown by rescue of aging-related left ventricular denervation (0.04±0.005 fold; p<0.0001) in the hearts of Vegfb186 treated old mice. However, heart to body weight ratio and cardiomyocyte hypertrophy were increased in the Vegfb168-treated mice hearts, without alteration of cardiac systolic function. These results suggest that Vegfb186 has pleiotropic effects in the heart. In vitro assays confirmed the in vivo findings as isolated rat cardiomyocytes displayed significant hypertrophy in the presence of recombinant VEGFB186. By contrast, recombinant VEGFB186 blunted TGF-beta-2 mediated fibroblast activation in vitro. Although VEGFB186 had no direct effect on neurite outgrowth in vitro, it prevented the regression of neurons cultured in supernatants of senescent endothelial cells. Cardiac single-nuclei RNA sequencing confirmed proliferative and anti-apoptotic effects of Vegfb186 on endothelial cells and cardiomyocytes respectively in vivo. 
In conclusion, our data reveals that Vegfb186 partially reverses pathological alterations in the aging heart. Despite the overall improvement of the age-related cardiac phenotype, the cardiac hypertrophy induced by VEGFB186 may limit the translational potential of VEGFB as an anti-aging therapeutic. 
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