Angiogenesis, a tightly regulated process of new blood vessel formation, is initiated when a select set of endothelial cells is stimulated to leave their quiescent state.1 These cells become hypermigratory and form sprouts that guide the direction of vascular network development.2 Formation of this ordered network depends on a regulated differentiation of the endothelial cells in which only specific endothelial cells can become sprouts. The consequence of dysregulation would be a failure to develop a cohesive vascular network. Examples of this can be seen in vascular diseases, such as CADASIL, and in tumor growth.3,4 Article, see p 1206 The vascular network forms when endothelial sprouts develop at the leading edge of the angiogenic front. These leading sprouts are known as the tip cells, characterized by filopodial expansions, which guide growth toward proangiogenic signals. Behind them are the stalk cells that provide a supporting network through proliferation and lumen formation. A critical component of angiogenesis is the maintenance of a proper balance between the number of tip and stalk cells. The endothelial tip–stalk gradient is established when vascular endothelial growth factor (VEGF) is sensed by the endothelium.5 Higher expression levels of VEGFR2/3 are found in tip cells, making them more responsive to VEGF stimulation and triggering the upregulation of the Notch ligand, Delta-like 4 (DLL4). The DLL4 produced by the tip cell signals to Notch …