Notch Ligand Inhibits Angiogenesis

Oxford, UK -

The notch signalling pathway has been widely studied in development and tissue specification.  Notch acts as a receptor for various ligands and upon binding translocates into the nucleus to induce expression of various genes.  Two ligands of notch, Delta and Serrate have been implicated in the inhibition of stem cell differentiation. 

Previous studies have also demonstrated that Notch ligands, especially Delta-like 4, are involved in the inhibition of angiogenic proliferation but strengthening of the blood vessels that are already formed.  

In a recent study (Williams et al. Regulation of CXCR4 by the Notch ligand delta-like 4 in endothelial cells. Cancer Res 2008 Mar 15;68(6):1889-95) the effects of delta-like 4 on angiogenesis were examined in more detail. 

The investigators transfected HUVECs with the delta-like 4 protein (notch ligand) and demonstrated that the HUVEC had decreased migration to SDF-1 gradients, which was associated with reduction in CXCR-4.

Since notch requires gamma secretase activity of the cell in order for it to translocate to the nucleus and mediate its activities, the researchers administered a gamma secretase inhibitor to HUVEC cells stimulated with delta-like 4 to see if they could restore CXCR-4 expression.  A dose dependent rescue of expression and chemotactic activity was observed.

This study suggests that delta-like 4 inhibits certain aspects of angiogenesis by suppressing ability of endothelial cells to migrate in response to CXCR-4 ligands such as SDF-1.  This is important because mobilizers such as AMD 3100 actually function by inhibiting CXCR-4.  Therefore modulation of stem cell, or at least endothelial cell, homing may be possible by interfering with the delta-like 4-Notch pathway.