Background: Recent studies have shown that in the devoloping embryo, arterial and venous identity is established by genetic mechanism before circulation begins. Vascular endothelial growth factor (VEGF) signaling and its downstream Notch pathway play critical roles in arterial cell fate determination. We have recently shown that Foxc1 and Fox2, two closely related Fox transciption factors, are essential for arterial cell specification during development by directly inducing the transcription of Delta-like 4 (Dll4), a ligand for Notch receptors. However, the basic mechanism whereby the VEGF and Notch signaling pathways controls transcriptions regulation of arterial-specific genes have yet to be elucidated. Methodologies/Principals Findings: In the current study, we examined wether and how Foxc transcription factors are involved in VEGF and Notch signaling in including of Dll4 as well as the Notch target gene Hey2 in endothelial cells. We found that Foxc1 and Foxc2 directly activate the Hey2 promoter via Foxc binding elements. Significantly, Foxc2 physically and functionally interacts with a Notch transcriptional activation complex containing Su(H) and Notch intracellular domain to induce Hey2 promoter activity. Moreover, activation of the Dll4 and Hey2 promoters is induced by VEGF in conjuction with either Foxc1 or Foxc2 more than by either component alone. VEGF-activated P13K and ERK intracellular pathways modulate the transcriptional activity of Foxc in Dll4 and Hey2 induction. Conclusion/Significance: Our new findings demonstrate that Foxc transcriptional factors interact with VEGF and Notch signaling to regulate arterial gene expression in multiple steps of the VEGF-Dll4-Notch-Hey2 signaling pathway.
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