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

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Item Type:Article
Title:Synchronization of endothelial Dll4-Notch dynamics switch blood vessels from branching to expansion
Creators Name:Ubezio, B. and Blanco, R.A. and Geudens, I. and Stanchi, F. and Mathivet, T. and Jones, M.L. and Ragab, A. and Bentley, K. and Gerhardt, H.
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.
Keywords:Brain Neoplasms, Cell Movement, Endothelial Cells, Gene Expression Regulation, Glioblastoma, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Messenger RNA, Mouse Embryonic Stem Cells, Neoplasm Transplantation, Notch Receptors, Pathologic Neovascularization, Physiologic Neovascularization, Physiological Feedback, Reporter Genes, Retina, Signal Transduction, Vascular Endothelial Growth Factor A, Animals, Mice
Publisher:eLife Sciences Publications
Page Range:e12167
Date:13 April 2016
Official Publication:https://doi.org/10.7554/eLife.12167
PubMed:View item in PubMed

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