Journal
NATURE CELL BIOLOGY
Volume 16, Issue 4, Pages 309-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb2926
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Funding
- Marie Curie FP7 people initiative Fellowship
- HFSP fellowship
- EPSRC [EP/I031758/1]
- Deutsche Forschungsgemeinschaft [SFB629]
- Max-Planck-Society
- Knut and Alice Wallenberg Foundation
- Association for International Cancer Research
- Cancer Research UK
- Lister Institute of Preventive Medicine
- Leducq transatlantic Network ARTEMIS
- ERC [311719]
- EPSRC [EP/I031758/1] Funding Source: UKRI
- European Research Council (ERC) [311719] Funding Source: European Research Council (ERC)
- Engineering and Physical Sciences Research Council [EP/I031758/1] Funding Source: researchfish
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Endothelial cells show surprising cell rearrangement behaviour during angiogenic sprouting; however, the underlying mechanisms and functional importance remain unclear. By combining computational modelling with experimentation, we identify that Notch/VEGFR-regulated differential dynamics of VE-cadherin junctions drive functional endothelial cell rearrangements during sprouting. We propose that continual flux in Notch signalling levels in individual cells results in differential VE-cadherin turnover and junctional-cortex protrusions, which powers differential cell movement. In cultured endothelial cells, Notch signalling quantitatively reduced junctional VE-cadherin mobility. In simulations, only differential adhesion dynamics generated long-range position changes, required for tip cell competition and stalk cell intercalation. Simulation and quantitative image analysis on VE-cadherin junctional patterning in vivo identified that differential VE-cadherin mobility is lost under pathological high VEGF conditions, in retinopathy and tumour vessels. Our results provide a mechanistic concept for how cells rearrange during normal sprouting and how rearrangement switches to generate abnormal vessels in pathologies.
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