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

• Published in: Nature cell biology Vol. 12; no. 10; pp. 943 - 953
• Main Authors: Gerhardt, Holger, Jakobsson, Lars, Franco, Claudio A, Bentley, Katie, Collins, Russell T, Ponsioen, Bas, Aspalter, Irene M, Rosewell, Ian, Busse, Marta, Thurston, Gavin, Medvinsky, Alexander, Schulte-Merker, Stefan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2010; Nature Publishing Group
• Subjects: 631/114/2397; 631/136/16; 631/80/86; Angiogenesis; Animals; Biology; Biomedical and Life Sciences; Cancer Research; Cell Biology; Cells; Competition; Computational Biology; Computer Simulation; Developmental Biology; Drosophila; Drosophila - metabolism; Endothelial Cells - cytology; Endothelial Cells - metabolism; Genetic aspects; Insects; Intracellular Signaling Peptides and Proteins - metabolism; Kinases; Laboratories; Life Sciences; Ligands; Medical research; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Microscopy; Neovascularization, Physiologic - physiology; Physiological aspects; Receptors, Notch - metabolism; Retinal Vessels - metabolism; Signal Transduction; Stem Cells; Vascular endothelial growth factor; Vascular Endothelial Growth Factor Receptor-1 - metabolism; Vascular Endothelial Growth Factor Receptor-2 - metabolism; Vertebrae; Zebrafish - embryology; United Kingdom > UK
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/ncb2103

Notch and vascular endothelial growth factor receptor (VEGFR) coordinates endothelial cells behaviour during angiogenesis sprouting although exactly how is uncertain. Endothelial cells dynamically compete for the leading position in a sprout through relative levels of Vegfr1 and Vegfr2 in a Notch dependent manner. 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.