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Abstract: A functional cardiovascular system is essential for normal vertebrate tissue homeostasis. Tissues become vascularised as organisms grow during embryonic development. Endothelial cells, the specialised epithelium lining vasculature, interface with many different cell types throughout development and adulthood, while maintaining their cell state. Vascular dysfunction is a key component of many diseases, such as cancer, peripheral vascular diseases, and diabetes. In such cases, vascular dysfunction is often underpinned by changes in endothelial cell behaviour, and ultimately cell state. Endothelial-to-mesenchymal transition (EndMT) causes endothelial cells to become fibroblast-like and contributes to disease progression. However, the role of both vasculature and EndMT in regenerative processes is not fully understood.

During appendage regeneration, a new vascular network forms. We showed that inhibition of VEGF signalling blocks axolotl limb regeneration and causes a decrease in EMT-associated gene expression. Moreover, endothelial cells within the regenerating blastema display increased expression of EndMT- and EMT-associated genes, during normal axolotl limb regeneration, suggesting this process may be utilised in a pro-regenerative manner, as has been documented during zebrafish cardiac valve regeneration. Therefore, a better understanding of differences in endothelial regulation in highly regenerative species, from development to adulthood, compared to humans is necessary. Such insights may provide information on how endothelial cells can be manipulated for regenerative medicine therapies.