Endothelial signalling by the Notch ligand Delta-like 4 restricts angiogenesis

Notch signalling by the ligand Delta-like 4 (DII4) is essential for normal vascular remodelling, yet the precise way in which the pathway influences the behaviour of endothelial cells remains a mystery. Using the embryonic zebrafish, we show that, when DII4-Notch signalling is defective, endothelial cells continue to migrate and proliferate when they should normally stop these processes. Artificial overactivation of the Notch pathway has opposite consequences. When vascular endothelial growth factor (Vegf) signalling and DII4-Notch signalling are both blocked, the endothelial cells remain quiescent. Thus, DII4-Notch signalling acts as an angiogenic 'off' switch by making endothelial cells unresponsive to Vegf.