Beneficial effects of vascular endothelial growth factor B gene transfer in the aged heart

Members of the VEGF family are crucial modulators of vascular and neural function. While VEGFA signalling has been shown to mitigate several aging-related cardiac phenotypes and prolong survival in aged mice, the role of VEGFB in cardiac aging remains underexplored. In this study, we identify a significant decline in Vegfb expression, particularly of its soluble isoform Vegfb₁₈₆, in aged mouse and human hearts. To assess the therapeutic potential of VEGFB in aging-associated cardiac pathologies, we used AAV9-mediated gene transfer to overexpress Vegfb₁₈₆ in 18-month-old male C57Bl/6J mice.

VEGFB is known to exhibit vascular and neuroprotective effects that we assessed in the ageing heart. In the aged heart, doses of Vegfb₁₈₆ overexpression that had only a modest effect on the vascular endothelium prevented age-induced diastolic dysfunction and fibrosis. Vegfb186 treatment additionally restored sympathetic and sensory nerve fibre density and increased heart rate variability. Although Vegfb₁₈₆ overexpression induced cardiac hypertrophy, our findings indicated that this hypertrophy was compensatory rather than pathological as Vegfb₁₈₆ overexpression corrected the elevated cardiomyocyte length-to-width ratio observed in aged hearts, a metric typically indicative of pathological remodelling. Cardiac single-nucleus RNA sequencing of the hearts and in vitro analysis of the cardiomyocytes indicated up-regulation of the STAT3 signal transduction pathway as a potential contributor of VEGFB-induced cardiac hypertrophy.

Our findings demonstrate that Vegfb₁₈₆ overexpression partially reverses age-related cardiac pathologies such as diastolic dysfunction and fibrosis. This work highlights VEGFB as a potential therapeutic target for combating cardiac aging and its associated dysfunctions.