VEGF signaling promotes blastema growth and proliferation of vascular and non-vascular cells during axolotl limb regeneration.

Salamanders are capable of regenerating whole limbs throughout life, a feat that is unmatched by other tetrapods. Limb regeneration is dependent upon the formation of a blastema containing progenitor cells which give rise to most tissues of the regenerated limb. Many signaling pathways, including FGF, BMP and Wnt, are required for regeneration, but the role of VEGF signaling during salamander limb regeneration is not well understood, particularly outside of angiogenesis. Here we show that VEGF signaling is essential for limb regeneration and that blastema cells and limb fibroblasts display impaired proliferation in the absence of VEGF signaling. Loss of VEGF signaling reduces expression of EMT-associated genes, suggesting VEGF signaling promotes expression of EMT-associated transcription factors, including Snai2, during axolotl limb regeneration. These findings highlight potential roles for VEGF signaling during regeneration which may extend beyond its expected pro-angiogenic function.