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

Aims: 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...

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Main Authors: Manickam, Nivethitha (Author) , Sultan, Ibrahim (Author) , Panthel, Josefine (Author) , Kujundzic, Haris (Author) , Fischer, Ariane (Author) , Schmitz, Katja (Author) , Jurado, Mariano Ruz (Author) , Morales, David Rodriguez (Author) , John, David (Author) , Glaser, Simone-Franziska (Author) , Stilz, Kathrin A. (Author) , Malacarne, Pedro Felipe (Author) , Brandes, Ralf Peter (Author) , Braun, Thomas (Author) , Lerchenmüller, Carolin (Author) , Betge, Fynn (Author) , Abplanalp, Wesley T. (Author) , Alitalo, Kari (Author) , Dimmeler, Stefanie (Author) , Wagner, Julian Uwe Gabriel (Author)
Format: Article (Journal)
Language:English
Published: March 2025
In: Cardiovascular research
Year: 2025, Volume: 121, Issue: 10, Pages: 1594-1608
ISSN:1755-3245
DOI:10.1093/cvr/cvaf046
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1093/cvr/cvaf046
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Author Notes:Nivethitha Manickam, Ibrahim Sultan, Josefine Panthel, Haris Kujundzic, Ariane Fischer, Katja Schmitz, Mariano Ruz Jurado, David Rodriguez Morales, David John, Simone-Franziska Glaser, Kathrin A. Stilz, Pedro Felipe Malacarne, Ralf Peter Brandes, Thomas Braun, Carolin Lerchenmueller, Fynn Betge, Wesley T. Abplanalp, Kari Alitalo, Stefanie Dimmeler, and Julian U. G. Wagner
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Summary:Aims: 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.Methods and results: 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.Conclusion: 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.
Item Description:Online, ahead-of-print veröffentlicht: 21 März 2025
Gesehen am 26.04.2026
Physical Description:Online Resource
ISSN:1755-3245
DOI:10.1093/cvr/cvaf046

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