Figure 2. Cellular mechanisms of angiogenic sprouting.

a | In the absence of pro-angiogenic stimuli, endothelial cells (ECs) are retained in a quiescent state. In addition, EC homeostasis is maintained by low-level autocrine vascular endothelial growth factor A (VEGFA) signalling¹²⁴. b | During angiogenesis, high levels of exogenous pro-angiogenic factors (such as VEGFA and VEGFC) and of VEGF receptor 2 (VEGFR2) or VEGFR3 signalling select ‘tip cells’ (TCs; blue) for sprouting. By contrast, Delta-like 4–Notch signalling laterally inhibits TC fate in adjacent ECs. TC sprouting behaviour is facilitated by the vascular endothelial cadherin-mediated loosening of EC–EC junctions, matrix metalloproteinase-mediated degradation of extracellular matrix (ECM) and the detachment of pericytes (purple). c | Invasive TC sprouting is guided by gradients of pro-angiogenic growth factors and various environmental guidance cues, such as semaphorins and ephrins. During sprout elongation, TCs are trailed by endothelial ‘stalk cells’ (SCs; yellow), which maintain connectivity with parental vessels and initiate partitioning-defective 3 (PAR3)-mediated vascular lumen morphogenesis. Expression of VEGFR1 and activation of Notch, Roundabout homologue 4 and WNT signalling in SCs repress TC behaviour to maintain the hierarchical organization of sprouting ECs. However, TCs and SCs may also shuffle and exchange positions during angiogenic sprouting. Upon contact with other vessels, TC behaviour is repressed and vessels fuse by the process of anastomosis, which is assisted by associated myeloid cells. d | Nascent perfused vessels are subsequently stabilized by the platelet-derived growth factor B-mediated recruitment of supporting pericytes, the strengthening of EC–EC contacts and the deposition of an ECM to re-establish a quiescent endothelial phenotype. ANG2, angiopoietin 2.