The Notch Ligands Dll4 and Jagged1 Have Opposing Effects on Angiogenesis

Abstract

The Notch pathway is a highly conserved signaling system that controls a diversity of growth, differentiation, and patterning processes. In growing blood vessels, sprouting of endothelial tip cells is inhibited by Notch signaling, which is activated by binding of the Notch receptor to its ligand Delta-like 4 (Dll4). Here, we show that the Notch ligand Jagged1 is a potent proangiogenic regulator in mice that antagonizes Dll4-Notch signaling in cells expressing Fringe family glycosyltransferases. Upon glycosylation of Notch, Dll4-Notch signaling is enhanced, whereas Jagged1 has weak signaling capacity and competes with Dll4. Our findings establish that the equilibrium between two Notch ligands with distinct spatial expression patterns and opposing functional roles regulates angiogenesis, a mechanism that might also apply to other Notch-controlled biological processes.

Cross-talk between endothelial cells and tumor via delta-like ligand4/Notch/PTEN signaling inhibits lung cancer growth

“…Dll4 is usually upregulated by vascular endothelial growth factor in endothelial tip cells, which possess high Dll4 and low Notch (Patel et al, 2005;Hofmann and Luisa Iruela-Arispe, 2007;Benedito et al, 2009). The enhanced Dll4 could activate Notch in the adjacent stalk cells, which exhibit high Notch and low Dll4 (Hofmann and Luisa Iruela-Arispe, 2007;Phng and Gerhardt, 2009).…”

The Wnt pathway and the roles for its antagonists, DKKS, in angiogenesis

“…2). Interestingly, endothelial cell-specific Dkk-2 Tg mice display a vascular phenotype similar to Jag-1 Tg mice (74), and Jag-1 promotes Dkk-2 expression through Notch in human small intestine stem cells (75). These results imply that Dkk-2 might regulate angiogenic activity of endothelial cells through crosstalk with Notch signaling.…”

JAG2 Induction in Hypoxic Tumor Cells Alters Notch Signaling and Enhances Endothelial Cell Tube Formation

“…The mechanism behind the extension/formation of the new vasculature has been a recent subject of intense interest and has led to development of VEGF inhibitors for antiangiogenic tumor therapies. Recent studies have also unveiled the pivotal importance of Notch signaling in the process of angiogenesis, with specific focus on 2 Notch ligands DLL4 and JAG1 (5,(38)(39)(40)(41)(42). It is suggested that branching of new vasculature is a result of modulation of Notch signaling within the endothelial cells.…”