The role of differential VE-cadherin dynamics in cell rearrangement during angiogenesis

Katie Bentley; Claudio Areias Franco; Andrew Philippides; Raquel Blanco; Martina Dierkes; Véronique Gebala; Fabio Stanchi; Martin Jones; Irene M. Aspalter; Guiseppe Cagna; Simone Weström; Lena Claesson-Welsh; Dietmar Vestweber; Holger Gerhardt

doi:10.1038/ncb2926

The role of differential VE-cadherin dynamics in cell rearrangement during angiogenesis

Katie Bentley^*
, Claudio Areias Franco
, Andrew Philippides
, Raquel Blanco
, Martina Dierkes
, Véronique Gebala
, Fabio Stanchi
, Martin Jones
, Irene M. Aspalter
, Guiseppe Cagna
, Simone Weström
, Lena Claesson-Welsh
, Dietmar Vestweber
, Holger Gerhardt

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

300 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	309-321
Number of pages	13
Journal	Nature Cell Biology
Volume	16
Issue number	4
DOIs	https://doi.org/10.1038/ncb2926
Publication status	Published - Apr 2014
Externally published	Yes

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10.1038/ncb2926

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@article{73912bfe10f54fa6b39d53170bd38784,

title = "The role of differential VE-cadherin dynamics in cell rearrangement during angiogenesis",

abstract = "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.",

author = "Katie Bentley and Franco, \{Claudio Areias\} and Andrew Philippides and Raquel Blanco and Martina Dierkes and V{\'e}ronique Gebala and Fabio Stanchi and Martin Jones and Aspalter, \{Irene M.\} and Guiseppe Cagna and Simone Westr{\"o}m and Lena Claesson-Welsh and Dietmar Vestweber and Holger Gerhardt",

note = "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.",

year = "2014",

month = apr,

doi = "10.1038/ncb2926",

language = "English",

volume = "16",

pages = "309--321",

journal = "Nature Cell Biology",

issn = "1465-7392",

publisher = "Nature Research",

number = "4",

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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 - https://www.scopus.com/pages/publications/84897536435

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 -

The role of differential VE-cadherin dynamics in cell rearrangement during angiogenesis

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