VEGF and Notch signaling: the yin and yang of angiogenic sprouting

Tubular sprouting in angiogenesis relies on division of labour between endothelial tip cells, leading and guiding the sprout, and their neighboring stalk cells, which divide and form the vascular lumen. We previously learned how the graded extracellular distribution of heparin-binding vascular endothelial growth factor (VEGF)-A orchestrates and balances tip and stalk cell behavior. Recent data now provided insight into the regulation of tip cell numbers, illustrating how delta-like (DII)4-Notch signalling functions to limit the explorative tip cell behavior induced by VEGF-A. These data also provided a first answer to the question why not all endothelial cells stimulated by VEGF-A turn into tip cells. Here we review this new model and discuss how VEGF-A and DII4/Notch signalling may interact dynamically at the cellular level to control vascular patterning.