Vascular endothelial growth factor-D (VEGFD) is a potent pro-lymphangiogenic molecule of tumour growth and is considered a
key therapeutic target to modulate metastasis. Despite roles in pathological neo-lymphangiogenesis, the characterisation of
an endogenous role for VEGFD in vascular development has remained elusive. Here, we used zebrafish to assay for genetic interactions
between the Vegf/Vegf-receptor pathway and SoxF transcription factors and identified a specific interaction between Vegfd
and Sox18. Double knockdown zebrafish embryos for Sox18/Vegfd and Sox7/Vegfd exhibit defects in arteriovenous differentiation.
Supporting this observation, we found that Sox18/Vegfd double but not single knockout mice displayed dramatic vascular development defects. We find that VEGFD-MEK-ERK signalling
modulates SOX18-mediated transcription, functioning at least in part by enhancing nuclear concentration and transcriptional
activity in vascular endothelial cells. This work suggests that VEGFD-mediated pathologies include or involve an underlying
dysregulation of SOXF-mediated transcriptional networks.