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The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching

Item Type:Article
Title:The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching
Creators Name:Suchting, S. and Freitas, C. and le Noble, F. and Benedito, R. and Breant, C. and Duarte, A. and Eichmann, A.
Abstract:Delta-like 4 (Dll4) is a transmembrane ligand for Notch receptors that is expressed in arterial blood vessels and sprouting endothelial cells. Here we show that Dll4 regulates vessel branching during development by inhibiting endothelial tip cell formation. Heterozygous deletion of dll4 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 dll4(+/-) retinal vessels required the vascular growth factor VEGF and was inhibited when VEGF signaling was blocked. Although VEGF expression was not significantly altered in dll4(+/-) retinas, dll4(+/-) vessels showed increased expression of VEGF receptor 2 and decreased expression of VEGF receptor 1 compared with wild- type, suggesting they could be more responsive to VEGF stimulation. In addition, expression of dll4 in wild-type tip cells was itself decreased when VEGF signaling was blocked, indicating that dll4 may act downstream of VEGF as a 'brake' on VEGF-mediated angiogenic sprouting. Taken together, these data reveal Dll4 as a negative regulator of vascular sprouting and vessel branching that is required for normal vascular network formation during development.
Keywords:Angiogenesis, Vascular development, VEGF, Sprouting, Guidance
Source:Proceedings of the National Academy of Sciences of the United States of America
ISSN:0027-8424
Publisher:National Academy of Sciences (U.S.A.)
Volume:104
Number:9
Page Range:3225-3230
Date:27 February 2007
Official Publication:https://doi.org/10.1073/pnas.0611177104
PubMed:View item in PubMed

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