Delta-like ligand 4 (Dll4) is induced by VEGF as a negative regulator of angiogenic sprouting

TLDR

Genetic deletion studies show that haploinsufficiency of Dll4 causes major vascular defects and embryonic lethality. The study aims to define Dll4’s role during vascular growth and differentiation using the postnatal retina as a model. The authors assessed Dll4 expression dynamics and manipulated Dll4/Notch signaling in the postnatal retina with genetic deletion and pharmacologic inhibition. Dll4 is induced by VEGF and functions as a negative feedback regulator that limits angiogenic sprouting, ensuring proper vascular network formation while its blockade enhances sprouting and vessel regrowth but suppresses pathological neovascularization.

Abstract

Genetic deletion studies have shown that haploinsufficiency of Delta-like ligand (Dll) 4, a transmembrane ligand for the Notch family of receptors, results in major vascular defects and embryonic lethality. To better define the role of Dll4 during vascular growth and differentiation, we selected the postnatal retina as a model because its vasculature develops shortly after birth in a highly stereotypic manner, during which time it is accessible to experimental manipulation. We report that Dll4 expression is dynamically regulated by VEGF in the retinal vasculature, where it is most prominently expressed at the leading front of actively growing vessels. Deletion of a single Dll4 allele or pharmacologic inhibition of Dll4/Notch signaling by intraocular administration of either soluble Dll4-Fc or a blocking antibody against Dll4 all produced the same set of characteristic abnormalities in the developing retinal vasculature, most notably enhanced angiogenic sprouting and increased endothelial cell proliferation, resulting in the formation of a denser and more highly interconnected superficial capillary plexus. In a model of ischemic retinopathy, Dll4 blockade also enhanced angiogenic sprouting and regrowth of lost retinal vessels while suppressing ectopic pathological neovascularization. Our data demonstrate that Dll4 is induced by VEGF as a negative feedback regulator and acts to prevent overexuberant angiogenic sprouting, promoting the timely formation of a well differentiated vascular network.