Notch ligands in endothelial differentiation

Los Angeles, CA -

Formation of new blood vessels from existing vessels, a process called "angiogenesis" is very useful for the therapy of diseases such as myocardial ischemia or critical limb ischemia. On the other side of the coin, knowing how to inhibit angiogenesis is critical for treatment of diseases such as cancer which are dependent on production of new blood vessels in order to feed the ever-growing tumor mass.

Notch protein is a receptor known to possess several ligands including Jagged and Delta-like. Notch and its ligands are involved in numerous biological processes ranging from cell fate differentiation/specification to immune regulation.

In a recent paper (Scehnet et al. Inhibition of Dll4 mediated signaling induces proliferation of immature vessels and results in poor tissue perfusion. Blood. 2007 Feb 20;) it was demonstrated that the Notch ligand Dll4 inhibits angiogenic proliferation but increases the strength of blood vessels. Through inhibiting the Notch-Dll4 pathway, the investigators demonstrated increased vascular proliferation but defective maturation of blood vessels that were leaky and did not provide proper perfusion.

Since others have already published that Notch-Dll4 inhibition induces tumor regression through stimulation of "defective" angiogenesis (Noguera-Troise et al. Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature. 2006 Dec 21;444(7122):1032-7.) it appears that this could be a fruitful signalling pathway for inhibition during development of cancer therapies.