The Notch ligand delta-like protein 4 (DLL4) is expressed highly and selectively within the arterial endothelium and has been shown to function as a ligand for Notch1 and Notch4. It is induced by VEGF as a negative feedback regulator and acts to prevent overexuberant angiogenic sprouting, pro-moting the timely formation of a well differentiated vascular network. DLL4-Notch1 signaling regulates the formation of appropriate numbers of tip cells to control vessel sprouting and branching in the mouse retina.