Fig. 7

Negative regulation and fine-tuning of VEGFR2-mediated signaling pathways. a VE-PTP regulates TIE2 and VEGFR2 dephosphorylation to balance angiogenic signaling and support vessel integrity. Activin A enhances VE-PTP expression and reduces VEGF-induced permeability, which may help control excessive vessel leakage in conditions such as diabetic retinopathy. b PTP1B regulates VEGFR2 signaling by binding to its cytoplasmic domain and dephosphorylating it, thereby acting as a negative regulator. c SHP1 acts as a negative regulator of VEGFR2 by dephosphorylating key tyrosine residues (Y996, Y1059, and Y1175) essential for endothelial cell proliferation. d TSP-1 modulates VEGFR2 activity by binding to CD36 and recruiting SHP1, which dephosphorylates VEGFR2 at Y1175. This action suppresses VEGF signaling and inhibits angiogenesis. e Notch signaling coordinates angiogenesis by balancing the roles of tip and stalk cells. Dll4 on tip cells activates Notch in stalk cells, reducing VEGFR expression and VEGF sensitivity to stabilize newly formed vessels. Fringe, a glycosyltransferase in stalk cells, enhances Dll4-Notch signaling, further reducing VEGFR levels and reinforcing stalk cell quiescence. Meanwhile, Jagged1 counteracts Dll4 by modulating Notch in stalk cells, allowing some cells to remain responsive to VEGF, supporting sprouting. This interplay ensures selective sprouting while maintaining vessel stability. Notably, the Notch-VEGFR3 pathway can also promote angiogenesis independently of VEGF-A/VEGFR2. VE-PTP vascular endothelial protein tyrosine phosphatase, VEGFR vascular endothelial growth factor receptor, PTP1B protein tyrosine phosphatase 1B, SHP-1 Src homology 2 domain-containing phosphatase-1, TSP-1 Thrombospondin-1. Created in BioRendender.com