Endocrine Abstracts

While it is well established that vascular endothelial growth factor-A (VEGF) is an indispensable mediator of normal and pathological angiogenesis, other molecules in the local microenvironment play important roles in modulating the proangiogenic effects of VEGF. For example, Notch receptors are expressed in the vasculature and genetic deletion of Notch1 or key downstream signaling elements results in embryonic lethality associated with vascular remodeling defects. Although most Notch receptors and ligands are expressed in many tissue and cell types, delta-like ligand 4 (Dll4) is largely restricted to the vascular endothelium, where it is most highly expressed in mature arteries and in actively growing vessels. Of the many genes known to be involved in vasculogenesis and angiogenesis, haploid insufficiency results in embryonic lethality only for Dll4 and VEGF, confirming that Dll4 is the Notch ligand most critically and specifically involved in the development of the vascular system.

To more clearly define the role of Dll4, we evaluated the effect of genetic deletion or pharmacological inhibition of Dll4 on normal and pathological angiogenesis in the retina. The expression of Dll4 is upregulated by VEGF in actively growing blood vessels. Inhibition of Dll4/Notch signaling increased angiogenic sprouting and endothelial cell proliferation during normal retinal angiogenesis, resulting in the formation of an exceptionally dense, highly interconnected capillary plexus. In the murine model of oxygen-induced ischemic retinopathy (OIR), Dll4 blockade also enhanced angiogenic sprouting, resulting in a more effective regrowth of lost retinal vessels, while decreasing the development of ectopic, pathological neovascularization. These and other observations indicate that Dll4/Notch signalling acts as a negative feedback regulator of VEGF-induced vascular sprouting and proliferation. We hypothesize that by appropriately restraining VEGF-induced angiogenesis, Dll4 normally acts in concert with VEGF and other local cues to promote the timely formation and differentiation of competent vascular networks.

DLL4 modulates VEGF’s actions in diverse forms of pathological angiogenesis. For example, VEGF also strongly induces Dll4 expression in tumors blood vessels. Here, blockade of Dll4/Notch signaling can retard tumor growth by enhancing the chaotic, non-productive vascular sprouting characteristic of tumor angiogenesis. Thus, pharmacological modulation of Dll4/Notch signaling may have therapeutic applications in diverse diseases affecting vascular structure and function.