Redirecting full-length FLT1 expression towards its soluble isoform promotes postischemic angiogenesis

Bundalo, M.; Vorlova, S.; Ulrich, J.; Barbieri, R.; Richter, L.; Hoena, L.; Egg, M.; Bock, J.; Schaefer, S.; Amezaga Sole, N.; Rosa, A.; Rizzo, G.; Cochain, C.; Kastenmueller, W.; Henke, E.; Skryabin, B. V.; Rozhdestvensky, T. S.; Wildgruber, M.; Lorenz, K.; Kuhn, M.; Zernecke, A.

doi:10.1101/2024.09.19.613989

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bioRxiv · 10.1101/2024.09.19.613989

Redirecting full-length FLT1 expression towards its soluble isoform promotes postischemic angiogenesis

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Abstract

Vascular endothelial growth factors and their tyrosine kinase receptors are key mediators of vasculogenesis and angiogenesis with FLT1 (VEGFR1) serving as a decoy receptor. A truncated mRNA transcript encoding soluble (s) FLT1 can be generated by premature cleavage and polyadenylation (APA). Although a shortening of transcripts is described in pathological settings, including heart diseases, the functional in vivo impact of FLT1 gene isoform generation and relevance for angiogenesis remain unknown. Here, we show that specific splice site mutations within Flt1 inhibit telescripting and activate APA in vivo to efficiently modulate gene isoform expression, inducing a complete loss of full-length (fl) Flt1 and a switch towards sFlt1 in mice. FLT1 is a high-affinity decoy receptor of VEGF limiting vessel overgrowth. We show that sFLT1 was sufficient for developmental vasculogenesis, whereas flFLT1 controlled ischemia-driven angiogenesis. Our results demonstrate that telescripting is essential in vivo for controlling Flt1 isoform expression and angiogenesis and can be harnessed to improve reparative revascularization. Furthermore, given the widespread abundance of APA signals, our approach may serve as a blueprint for studying telescripting and generating other truncated gene isoforms in vivo.

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Bundalo, M., Vorlova, S., Ulrich, J., Barbieri, R., Richter, L., Hoena, L., Egg, M., Bock, J., Schaefer, S., Amezaga Sole, N., Rosa, A., Rizzo, G., Cochain, C., Kastenmueller, W., Henke, E., Skryabin, B. V., Rozhdestvensky, T. S., Wildgruber, M., Lorenz, K., Kuhn, M., Zernecke, A.. 2024-09-20. Redirecting full-length FLT1 expression towards its soluble isoform promotes postischemic angiogenesis. https://doi.org/10.1101/2024.09.19.613989

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