Endothelial cells dynamically compete for the tip cell position during angiogenic sprouting

被引：724

作者：

Jakobsson, Lars ^{[1
]}

Franco, Claudio A. ^{[1
]}

Bentley, Katie ^{[1
]}

Collins, Russell T. ^{[1
]}

Ponsioen, Bas ^{[2
]}

Aspalter, Irene M. ^{[1
]}

Rosewell, Ian ^{[3
]}

Busse, Marta ^{[1
]}

Thurston, Gavin ^{[4
]}

Medvinsky, Alexander ^{[5
]}

Schulte-Merker, Stefan ^{[2
]}

Gerhardt, Holger ^{[1
,6
]}

机构：

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

[2] Hubrecht Inst, NL-3584 CT Utrecht, Netherlands

[3] Canc Res UK, Clare Hall Labs, London Res Inst, Transgen Serv, Potters Bar EN6 3LD, Herts, England

[4] Regeneron Pharmaceut Inc, Tarrytown, NY 10591 USA

[5] MRC, Ctr Regenerat Med, Edinburgh EH16 4SB, Midlothian, Scotland

[6] Vesalius Res Ctr, Vasc Patterning Lab, O&N1, B-3000 Louvain, Belgium

来源：

NATURE CELL BIOLOGY | 2010年 / 12卷 / 10期

关键词：

m; TYROSINE KINASE; GROWTH-FACTOR; IN-VIVO; NOTCH; VEGF; FLT-1; EMBRYOS; BINDING; DLL4; VASCULOGENESIS;

D O I：

10.1038/ncb2103

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Sprouting angiogenesis requires the coordinated behaviour of endothelial cells, regulated by Notch and vascular endothelial growth factor receptor (VEGFR) signalling. Here, we use computational modelling and genetic mosaic sprouting assays in vitro and in vivo to investigate the regulation and dynamics of endothelial cells during tip cell selection. We find that endothelial cells compete for the tip cell position through relative levels of Vegfr1 and Vegfr2, demonstrating a biological role for differential Vegfr regulation in individual endothelial cells. Differential Vegfr levels affect tip selection only in the presence of a functional Notch system by modulating the expression of the ligand Dll4. Time-lapse microscopy imaging of mosaic sprouts identifies dynamic position shuffling of tip and stalk cells in vitro and in vivo, indicating that the VEGFR-Dll4-Notch signalling circuit is constantly re-evaluated as cells meet new neighbours. The regular exchange of the leading tip cell raises novel implications for the concept of guided angiogenic sprouting.

引用

页码：943 / 953

页数：11

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