1. The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching
- Author
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Suchting, Steven, Freitas, Catarina, le Noble, Ferdinand, Benedito, Rui, Breant, Christiane, Duarte, Antonio, and Eichmann, Anne
- Subjects
Vascular endothelial growth factor -- Research ,Ligands (Biochemistry) -- Structure ,Ligands (Biochemistry) -- Research ,Neovascularization -- Research ,Science and technology - Abstract
Delta-like 4 (DII4) is a transmembrane ligand for Notch receptors that is expressed in arterial blood vessels and sprouting endothelial cells. Here we show that DII4 regulates vessel branching during development by inhibiting endothelial tip cell formation. Heterozygous deletion of dII4 or pharmacological inhibition of Notch signaling using [gamma]-secretase inhibitor revealed a striking vascular phenotype, with greatly increased numbers of filopodia- extending endothelial tip cells and increased expression of tip cell marker genes compared with controls. Filopodia extension in dII[4.sup.+/-] retinal vessels required the vascular growth factor VEGF and was inhibited when VEGF signaling was blocked. Although VEGF expression was not significantly altered in dII[4.sup.+/-] retinas, dII[4.sup.+/-] vessels showed increased expression of VEGF receptor 2 and decreased expression of VEGF receptor 1 compared with wildtype, suggesting they could be more responsive to VEGF stimulation. In addition, expression of dII4 in wild-type tip cells was itself decreased when VEGF signaling was blocked, indicating that dII4 may act downstream of VEGF as a 'brake' on VEGF-mediated angiogenic sprouting. Taken together, these data reveal DIM as a negative regulator of vascular sprouting and vessel branching that is required for normal vascular network formation during development. angiogenesis | vascular development | VEGF | sprouting | guidance
- Published
- 2007