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Endothelial cells dynamically compete for the tip cell position during angiogenic sprouting

Item Type:Article
Title:Endothelial cells dynamically compete for the tip cell position during angiogenic sprouting
Creators Name:Jakobsson, L., Franco, C.A., Bentley, K., Collins, R.T., Ponsioen, B., Aspalter, I.M., Rosewell, I., Busse, M., Thurston, G., Medvinsky, A., Schulte-Merker, S. and Gerhardt, H.
Abstract:Sprouting angiogenesis requires the coordinated behaviour of endothelial cells, regulated by Notch and vascular endothelial growth factor receptor (VEGFR) signalling. Here, we use computational modelling and genetic mosaic sprouting assays in vitro and in vivo to investigate the regulation and dynamics of endothelial cells during tip cell selection. We find that endothelial cells compete for the tip cell position through relative levels of Vegfr1 and Vegfr2, demonstrating a biological role for differential Vegfr regulation in individual endothelial cells. Differential Vegfr levels affect tip selection only in the presence of a functional Notch system by modulating the expression of the ligand Dll4. Time-lapse microscopy imaging of mosaic sprouts identifies dynamic position shuffling of tip and stalk cells in vitro and in vivo, indicating that the VEGFR-Dll4-Notch signalling circuit is constantly re-evaluated as cells meet new neighbours. The regular exchange of the leading tip cell raises novel implications for the concept of guided angiogenic sprouting.
Keywords:Computational Biology, Computer Simulation, Endothelial Cells, Inbred C57BL Mice, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Notch Receptors, Physiologic Neovascularization, Retinal Vessels, Signal Transduction, Vascular Endothelial Growth Factor Receptor-1, Vascular Endothelial Growth Factor Receptor-2, Animals, Drosophila, Mice, Zebrafish
Source:Nature Cell Biology
Publisher:Nature Publishing Group
Page Range:943-953
Date:October 2010
Official Publication:https://doi.org/10.1038/ncb2103
PubMed:View item in PubMed

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