Distinct Vegfa Isoforms Control Endothelial Cell Proliferation Through PI3 Kinase Signaling Mediated Regulation of cdkn1a/P21

The formation of appropriately patterned blood vessel networks requires endothelial cell migration and proliferation. Signaling through the Vascular Endothelial Growth Factor A (VEGFA) pathway is instrumental in coordinating these processes. mRNA splicing generates short (diffusible) and long (extracellular matrix bound) Vegfa isoforms. The differences between these isoforms in controlling cellular functions are not understood. In zebrafish, vegfaa generates short and long isoforms, while vegfab only generates long isoforms. We found that mutations in vegfaa affected endothelial cell migration and proliferation. Surprisingly, mutations in vegfab specifically reduced endothelial cell proliferation. Analysis of downstream signaling revealed no change in MAPK (ERK) activation, while inhibiting PI3 kinase signaling phenocopied vegfab mutants. The cell cycle inhibitor cdkn1a/p21 was upregulated in vegfab deficient embryos. Accordingly, reducing cdkn1a/p21 restored endothelial cell proliferation. Together, these results suggest that extracellular matrix bound Vegfa acts through PI3K signaling to specifically control endothelial cell proliferation during angiogenesis independently of MAPK (ERK) regulation.

Keywords: Zebrafish, angiogenesis, VEGF signaling, PI3 kinase signaling, cdkn1a/p21, endothelial cell proliferation

Suggested Citation: Suggested Citation

Lange, Martin and Leonard, Elvin and Ohnesorge, Nils and Hoffmann, Dennis and Rocha, Susanna and Benedito, Rui and Siekmann, Arndt Friedrich, Distinct Vegfa Isoforms Control Endothelial Cell Proliferation Through PI3 Kinase Signaling Mediated Regulation of cdkn1a/P21. Available at SSRN: https://ssrn.com/abstract=3588832 or http://dx.doi.org/10.2139/ssrn.3588832

This version of the paper has not been formally peer reviewed.