The role of differential VE-cadherin dynamics in cell rearrangement during angiogenesis
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Katie Bentley Claudio Areias Franco Andrew Philippides Raquel Blanco Martina Dierkes Véronique Gebala Fabio Stanchi Martin Jones Irene Aspalter Guiseppe Cagna Simone Weström Lena Claesson-Welsh Dietmar Vestweber Holger GerhardtAbstract
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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Publisher website (DOI) 10.1038/ncb2926
Europe PubMed Central 24658686
Pubmed 24658686
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