Open AccessDelta-like ligand 4 (Dll4) is induced by VEGF as a negative regulator of angiogenic sprouting
Author(s) -
Ivan B. Lobov,
R.A. Renard,
Nick Papadopoulos,
Nicholas W. Gale,
Gavin Thurston,
George D. Yancopouloš,
Stanley J. Wiegand
Publication year - 2007
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0611206104
Subject(s) - sprouting angiogenesis , notch signaling pathway , retinal , regulator , biology , microbiology and biotechnology , haploinsufficiency , angiogenesis , vascular endothelial growth factor a , cancer research , vascular endothelial growth factor , neovascularization , signal transduction , genetics , vegf receptors , phenotype , biochemistry , gene
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.