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

被引：285

作者：

Bentley, Katie ^{[1
]}

Franco, Claudio Areias ^{[1
]}

Philippides, Andrew ^{[2
]}

Blanco, Raquel ^{[1
]}

Dierkes, Martina ^{[3
]}

Gebala, Veronique ^{[1
]}

Stanchi, Fabio ^{[4
,5
]}

Jones, Martin ^{[1
]}

Aspalter, Irene M. ^{[1
]}

Cagna, Guiseppe ^{[3
]}

Westrom, Simone ^{[6
]}

Claesson-Welsh, Lena ^{[6
]}

Vestweber, Dietmar ^{[3
]}

Gerhardt, Holger ^{[1
,4
,5
]}

机构：

[1] Canc Res UK, London Res Inst, Vasc Biol Lab, London WC2A 3LY, England

[2] Univ Sussex, Dept Informat, Ctr Computat Neurosci & Robot, Brighton BN1 9QJ, E Sussex, England

[3] Max Planck Inst Mol Biomed, D-48149 Munster, Germany

[4] VIB3 Vesalius Res Ctr, Vasc Patterning Lab, B-3000 Louvain, Belgium

[5] CMVB, Dept Oncol, B-3000 Louvain, Belgium

[6] Uppsala Univ, Dept Immunol Genet & Pathol, Rudbeck Lab, S-75185 Uppsala, Sweden

来源：

NATURE CELL BIOLOGY | 2014年 / 16卷 / 04期

基金：

欧洲研究理事会; 英国工程与自然科学研究理事会;

关键词：

VASCULAR ENDOTHELIAL-CADHERIN; ADHESION HYPOTHESIS; REGULATES FORMATION; ADAPTER PROTEIN; IN-VIVO; MORPHOGENESIS; PERMEABILITY; PTP; ENDOCYTOSIS; SIMULATION;

D O I：

10.1038/ncb2926

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：309 / +

页数：41

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