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Negative regulators of vessel patterning

Item Type:Book Section
Title:Negative regulators of vessel patterning
Creators Name:Suchting, S. and Freitas, C. and Le Noble, F. and Benedito, R. and Breant, C. and Duarte, A. and Eichmann, A.
Abstract:Blood vessels and nerves are structurally similar, complex branched networks that require guidance to ensure their proper positioning in the body. Recent studies have demonstrated that specialized endothelial cells, resembling axonal growth cones, are located at the tips of growing capillaries. These endothelial tip cells guide outgrowing capillaries in response to gradients of extracellular matrix-bound vascular endothelial growth factor (VEGF). Here we show that endothelial tip cell formation and vessel branching are negatively regulated by the Notch ligand Delta-like 4 (Dll4). Heterozygous deletion of Dll4 or pharmacological inhibition of Notch signalling 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 to controls. Filopodia extension in Dll4+/- retinal vessels required VEGF and was inhibited when VEGF signalling was blocked. While 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 to wildtype, suggesting that they could be more responsive to VEGF stimulation. In addition, expression of Dll4 in wildtype tip cells was itself decreased when VEGF signalling 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 novel negative regulator of vascular sprouting and vessel branching that is required for normal vascular network formation during development.
Keywords:Vessel Patterning Negative Regulators, Notch Ligand Delta-Like 4 (Dll4), Normal Angiogenic Sprouting and VEGF, Dll4 - Vascular Sprouting Novel Negative Regulator, Notch Signalling, Animals, Mice
Source:Novartis Foundation Symposium
Series Name:Novartis Foundation Symposia
Title of Book:Novartis Foundation Symposium 283 - Vascular Development
ISSN:1528-2511
ISBN:9780470034286
Publisher:Wiley
Volume:283
Number:283
Page Range:77-80
Number of Pages:250
Date:11 September 2007
Official Publication:https://doi.org/10.1002/9780470319413.ch7
PubMed:View item in PubMed

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