Notch pathway targets proangiogenic regulator Sox17 to restrict angiogenesis.

The Notch pathway stabilizes sprouting angiogenesis by favoring stalk cells over tip cells at the vascular front. Because tip and stalk cells have different properties in morphology and function, their transcriptional regulation remains to be distinguished. Transcription factor Sox17 is specifically expressed in endothelial cells, but its expression and role at the vascular front remain largely unknown. To specify the role of Sox17 and its relationship with the Notch pathway in sprouting angiogenesis. Endothelial-specific Sox17 deletion reduces sprouting angiogenesis in mouse embryonic and postnatal vascular development, whereas Sox17 overexpression increases it. Sox17 promotes endothelial migration by destabilizing endothelial junctions and rearranging cytoskeletal structure and upregulates expression of several genes preferentially expressed in tip cells. Interestingly, Sox17 expression is suppressed in stalk cells in which Notch signaling is relatively high. Notch activation by overexpressing Notch intracellular domain reduces Sox17 expression both in primary endothelial cells and in retinal angiogenesis, whereas Notch inhibition by delta-like ligand 4 (Dll4) blockade increases it. The Notch pathway regulates Sox17 expression mainly at the post-transcriptional level. Furthermore, endothelial Sox17 ablation rescues vascular network from excessive tip cell formation and hyperbranching under Notch inhibition in developmental and tumor angiogenesis. Our findings demonstrate that the Notch pathway restricts sprouting angiogenesis by reducing the expression of proangiogenic regulator Sox17.

Lee SH ，Lee S ，Yang H ，Song S ，Kim K ，Saunders TL ，Yoon JK ，Koh GY ，Kim I ... -  《-》

Sox7, Sox17, and Sox18 Cooperatively Regulate Vascular Development in the Mouse Retina.

Zhou Y ，Williams J ，Smallwood PM ，Nathans J ... -  《PLoS One》

Synaptojanin-2 binding protein stabilizes the Notch ligands DLL1 and DLL4 and inhibits sprouting angiogenesis.

Adam MG ，Berger C ，Feldner A ，Yang WJ ，Wüstehube-Lausch J ，Herberich SE ，Pinder M ，Gesierich S ，Hammes HP ，Augustin HG ，Fischer A ... -  《-》

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

Goveia J ，Zecchin A ，Rodriguez FM ，Moens S ，Stapor P ，Carmeliet P ... -  《-》

SoxF Transcription Factors Are Positive Feedback Regulators of VEGF Signaling.

Vascular endothelial growth factor (VEGF) signaling is a key pathway for angiogenesis and requires highly coordinated regulation. Although the Notch pathway-mediated suppression of excessive VEGF activity via negative feedback is well known, the positive feedback control for augmenting VEGF signaling remains poorly understood. Transcription factor Sox17 is indispensable for angiogenesis, but its association with VEGF signaling is largely unknown. The contribution of other Sox members to angiogenesis also remains to be determined. To reveal the genetic interaction of Sox7, another Sox member, with Sox17 in developmental angiogenesis and their functional relationship with VEGF signaling. Sox7 is expressed specifically in endothelial cells and its global and endothelial-specific deletion resulted in embryonic lethality with severely impaired angiogenesis in mice, substantially overlapping with Sox17 in both expression and function. Interestingly, compound heterozygosity for Sox7 and Sox17 phenocopied vascular defects of Sox7 or Sox17 homozygous knockout, indicating that the genetic cooperation of Sox7 and Sox17 is sensitive to their combined gene dosage. VEGF signaling upregulated both Sox7 and Sox17 expression in angiogenesis via mTOR pathway. Furthermore, Sox7 and Sox17 promoted VEGFR2 (VEGF receptor 2) expression in angiogenic vessels, suggesting a positive feedback loop between VEGF signaling and SoxF. Our findings demonstrate that SoxF transcription factors are indispensable players in developmental angiogenesis by acting as positive feedback regulators of VEGF signaling.

Kim K ，Kim IK ，Yang JM ，Lee E ，Koh BI ，Song S ，Park J ，Lee S ，Choi C ，Kim JW ，Kubota Y ，Koh GY ，Kim I ... -  《-》