Robustness in angiogenesis: notch and BMP shaping waves.

Vascular patterning involves sprouting of blood vessels, which is governed by orchestrated communication between cells in the surrounding tissue and endothelial cells (ECs) lining the blood vessels. Single ECs are selected for sprouting by hypoxia-induced stimuli and become the 'tip' or leader cell that guides new sprouts. The 'stalk' or trailing ECs proliferate for tube extension and lumenize the nascent vessel. Stalk and tip cells can dynamically switch their identities during this process in a Notch-dependent manner. Here, we review recent studies showing that bone morphogenetic protein (BMP) signaling coregulates Notch target genes in ECs. In particular, we focus on how Delta-like ligand 4 (DLL4)-Notch and BMP effector interplay may drive nonsynchronized oscillatory gene expression in ECs essential for setting sharp tip-stalk cell boundaries while sustaining a dynamic pool of nonsprouting ECs. Deeper knowledge about the coregulation of vessel plasticity in different vascular beds may result in refinement of anti-angiogenesis and vessel normalization therapies.