Synchronization of endothelial Dll4-Notch dynamics switch blood vessels from branching to expansion

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Abstract

Formation of a regularly branched blood vessel network is crucial in development and physiology. Here we show that the expression of the Notch ligand Dll4 fluctuates in individual endothelial cells within sprouting vessels in the mouse retina in vivo and in correlation with dynamic cell movement in mouse embryonic stem cell-derived sprouting assays. We also find that sprout elongation and branching associates with a highly differential phase pattern of Dll4 between endothelial cells. Stimulation with pathologically high levels of Vegf, or overexpression of Dll4, leads to Notch dependent synchronization of Dll4 fluctuations within clusters, both in vitro and in vivo. Our results demonstrate that the Vegf-Dll4/Notch feedback system normally operates to generate heterogeneity between endothelial cells driving branching, whilst synchronization drives vessel expansion. We propose that this sensitive phase transition in the behaviour of the Vegf-Dll4/Notch feedback loop underlies the morphogen function of Vegfa in vascular patterning.

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Benedetta Ubezio

Vascular Biology Laboratory, London Research Institute, London, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Raquel Agudo Blanco

Vascular Biology Laboratory, London Research Institute, London, United Kingdom

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The authors declare that no competing interests exist.
Ilse Geudens

Vascular Patterning Laboratory, Vesalius Research Center, VIB, Leuven, Belgium

Competing interests
The authors declare that no competing interests exist.
Fabio Stanchi

Vascular Patterning Laboratory, Vesalius Research Center, VIB, Leuven, Belgium

Competing interests
The authors declare that no competing interests exist.
Thomas Mathivet

Vascular Patterning Laboratory, Vesalius Research Center, VIB, Leuven, Belgium

Competing interests
The authors declare that no competing interests exist.
Martin L Jones

Vascular Biology Laboratory, London Research Institute, London, United Kingdom

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The authors declare that no competing interests exist.
Anan Ragab

Vascular Biology Laboratory, London Research Institute, London, United Kingdom

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The authors declare that no competing interests exist.
Katie Bentley

Computational Biology Laboratory, Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States

Competing interests
The authors declare that no competing interests exist.
Holger Gerhardt

Vascular Biology Laboratory, London Research Institute, London, United Kingdom

For correspondence
holger.gerhardt@mdc-berlin.de

Competing interests
The authors declare that no competing interests exist.

Ethics

Animal experimentation: Mice were maintained at London Research Institute under standard husbandry conditions. All protocols were approved by the UK Home Office (P80/2391). Glioblastoma studies were performed at the Vesalius Research Center, VIB, KU Leuven where housing and all experimental animal procedures were performed in accordance with Belgian law on animal care and were approved by the Institutional Animal Care and Research Advisory Committee of the K. U. Leuven (P105/2012).

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.