@article{df1fccb802d549a1983d118ec62f2809,
title = "Endothelial cells dynamically compete for the tip cell position during angiogenic sprouting",
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.",
author = "Lars Jakobsson and Franco, {Claudio A.} and Katie Bentley and Collins, {Russell T.} and Bas Ponsioen and Aspalter, {Irene M.} and Ian Rosewell and Marta Busse and Gavin Thurston and Alexander Medvinsky and Stefan Schulte-Merker and Holger Gerhardt",
note = "Funding Information: We would like to thank the Cancer Research UK (CRUK) Light Microscopy facility, P. Jordan, the Protein Purification lab, S. Kjaer , J. Yang and J. Ure. We thank D. Barr and I. Moal for simulation and analysis work performed in the Biomolecular Modelling Laboratory CRUK, D. Sauvaget and J. Babbage for technical assistance and B. Thompson for comments on the manuscript. The authors are supported by CRUK, the Lister Institute of Preventive Medicine, the European Molecular Biology Organization (EMBO) Young Investigator Programme, the Fondation Leducq Transatlantic Network of Excellence ARTEMIS (H.G.), the Leukaemia Research Fund (to A.M.) and an EMBO long‑ term post‑doctoral fellowship (to L.J.). We thank J. van Rheenen for discussions and assistance on the SP5 microscope (Leica Microsystems; equipment grant from the Dutch Organization of Scientific Research; NOW, 175.010.2007.007). We also thank A. de Graaff (M.Sc.) and the Hubrecht Imaging Centre (HIC) for imaging support. B.P. and S.S.‑M. were supported by the Nederlandse Akademie van Wetenschappen (KNAW).",
year = "2010",
month = oct,
doi = "10.1038/ncb2103",
language = "English",
volume = "12",
pages = "943--953",
journal = "Nature Cell Biology",
issn = "1465-7392",
publisher = "Nature Research",
number = "10",
}
