DLK1: a novel negative regulator of angiogenesis?

This editorial refers to ‘The non-canonical NOTCH ligand DLK1 exhibits a novel vascular role as a strong inhibitor of angiogenesis’ by P. Rodriguez et al. , pp. 232–241, this issue. The Notch signalling pathway is pivotal in normal vascular development and post-natal angiogenesis. Cumulative evidence supports the involvement of three canonical Notch ligands—Delta-like 1 (Dll1), Delta-like 4 (Dll4), and Jagged-1 (Jag1)—in the angiogenesis process. They are believed to function as Notch signalling agonists/antagonists to regulate the position and behaviour of endothelial cells under activated conditions. For instance, tissue-derived vascular endothelial growth factor (VEGF) induces the expression of the Dll4 ligand on endothelial tip cells, which in turn activates Notch signalling in neighbouring endothelial ‘stalk’ cells and restricts the emergence of excessive sprouting through repression of VEGF receptors and consequent reduction in responsiveness to VEGF.1–4 Moreover, Jag1 reportedly acts as an antagonist of the Dll4/Notch signalling in stalk cells, helping them maintain their activated phenotype.5 In this context, the coordination of different components of the Notch signalling seems to be a key determinant for proper and functional neovascularization.6,7 …