TY - JOUR
T1 - The role of differential VE-cadherin dynamics in cell rearrangement during angiogenesis
AU - Bentley, Katie
AU - Franco, Claudio Areias
AU - Philippides, Andrew
AU - Blanco, Raquel
AU - Dierkes, Martina
AU - Gebala, Véronique
AU - Stanchi, Fabio
AU - Jones, Martin
AU - Aspalter, Irene M.
AU - Cagna, Guiseppe
AU - Weström, Simone
AU - Claesson-Welsh, Lena
AU - Vestweber, Dietmar
AU - Gerhardt, Holger
N1 - Funding Information:
This work was supported by Cancer Research UK, the Lister Institute of Preventive Medicine, the Leducq transatlantic Network ARTEMIS and the ERC starting grant REshape (311719). C.F. is supported by a Marie Curie FP7 people initiative Fellowship. R.B. is supported by a HFSP fellowship. AP was financially supported by EPSRC grant EP/I031758/1. G.C. and D.V. were supported by funds from the Deutsche Forschungsgemeinschaft (SFB629) and the Max-Planck-Society. L.C.W. and S.W. are supported by grants from the Knut and Alice Wallenberg Foundation and from the Association for International Cancer Research. We thank B. Cruys (KU Leuven) and C. Lewis (MIT) for comments on the manuscript. We thank R. Chaleil for his support and maintenance of the high-performance computing system.
PY - 2014/4
Y1 - 2014/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84897536435&partnerID=8YFLogxK
U2 - 10.1038/ncb2926
DO - 10.1038/ncb2926
M3 - Article
C2 - 24658686
SN - 1465-7392
VL - 16
SP - 309
EP - 321
JO - Nature Cell Biology
JF - Nature Cell Biology
IS - 4
ER -