Endothelial cell differentiation by SOX17: promoting the tip cell or stalking its neighbor instead?

Vessel sprouting relies on the differentiation of endothelial cells (ECs) into a migratory tip cell leading at the forefront, proliferating stalk cells elongating the vessel stalk, and quiescent phalanx cells lining the perfused vessel.1 The tip versus stalk cell balance is under the control of vascular endothelial growth factor (VEGF) and Notch signaling, respectively.1 During recent years, the transcription factor SRY-related HMG box 17 (SOX17) has emerged as a regulator of arterial (at the expense of venous) EC specification, but its role in inducing the tip versus stalk EC behavior remained incompletely defined. In this issue of Circulation Research , Lee et al2 identified SOX17 as an inducer of the tip cell phenotype and showed that Notch signaling suppresses SOX17 levels to promote a stalk cell phenotype (Figure). However, using similar genetic mouse models, another recent study reported noncongruent findings.3 Can we explain these divergent interpretations and what are the possible implications of these results? Figure. Scheme illustrating the proposed models of the mechanism of Sox17 in vessel sprouting according to Lee et al.2 Sox17 plays a central role in the induction of tip cell differentiation. Expression of Sox17 in tip cells induces tip cell behavior, whereas Notch signaling downregulates Sox17 in endothelial cells to induce stalk cell specification. These results contradict with previous observations from Corada et al3 (discussed in insets) who report that Sox17 is a tip cell suppressor, upstream, not downstream, of Notch signaling. Red arrows indicate novel regulatory pathways dissected by Lee et al.2 Ang2 indicates angiopoietin-2; Dll4, Delta-like 4; ESM1, endothelial cell-specific molecule 1; NICD, Notch intracellular domain; and VEGFR2, vascular endothelial growth factor receptor 2. Article, see p 215 Except for a brief period of embryonic vasculogenesis during which the primitive vascular plexus is established, tissues are vascularized …