VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling

被引：230

作者：

Tammela, Tuomas ^{[1
,2
]}

Zarkada, Georgia ^{[1
,2
]}

Nurmi, Harri ^{[1
,2
]}

Jakobsson, Lars ^{[3
]}

Heinolainen, Krista ^{[1
,2
]}

Tvorogov, Denis ^{[1
,2
]}

Zheng, Wei ^{[1
,2
]}

Franco, Claudio A. ^{[3
]}

Murtomaki, Aino ^{[1
,2
]}

Aranda, Evelyn ^{[4
]}

Miura, Naoyuki ^{[5
]}

Yla-Herttuala, Seppo ^{[6
,7
]}

Fruttiger, Marcus ^{[8
]}

Makinen, Taija ^{[1
,2
]}

Eichmann, Anne ^{[9
]}

Pollard, Jeffrey W. ^{[4
]}

Gerhardt, Holger ^{[3
,10
]}

Alitalo, Kari ^{[1
,2
]}

机构：

[1] Univ Helsinki, Res Programs Unit, Mol Canc Biol Lab, Inst Mol Med Finland, FIN-00014 Helsinki, Finland

[2] Univ Helsinki, Biomedicum Helsinki, Dept Pathol, Haartman Inst, FIN-00014 Helsinki, Finland

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

[4] Albert Einstein Coll Med, Dept Dev & Mol Biol, New York, NY 10461 USA

[5] Hamamatsu Univ Sch Med, Dept Biochem, Hamamatsu, Shizuoka 4313192, Japan

[6] Univ Kuopio, Dept Med, Kuopio 70211, Finland

[7] Univ Kuopio, AI Virtanen Inst, Kuopio 70211, Finland

[8] UCL, Inst Ophthalmol, London EC1V 9EL, England

[9] Coll France, INSERM, U833, F-75005 Paris, France

[10] VIB, Vesalius Res Ctr, Vasc Patterning Lab, B-3000 Louvain, Belgium

来源：

NATURE CELL BIOLOGY | 2011年 / 13卷 / 10期

基金：

欧洲研究理事会; 芬兰科学院;

关键词：

GROWTH-FACTOR-C; ENDOTHELIAL-CELLS; TUMOR ANGIOGENESIS; FACTOR RECEPTOR-3; VASCULAR MORPHOGENESIS; LYMPHATIC ENDOTHELIUM; EXTRACELLULAR-MATRIX; MONOCLONAL-ANTIBODY; LIGAND-BINDING; MOUSE EMBRYOS;

D O I：

10.1038/ncb2331

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Angiogenesis, the growth of new blood vessels, involves specification of endothelial cells to tip cells and stalk cells, which is controlled by Notch signalling, whereas vascular endothelial growth factor receptor (VEGFR)-2 and VEGFR-3 have been implicated in angiogenic sprouting. Surprisingly, we found that endothelial deletion of Vegfr3, but not VEGFR-3-blocking antibodies, postnatally led to excessive angiogenic sprouting and branching, and decreased the level of Notch signalling, indicating that VEGFR-3 possesses passive and active signalling modalities. Furthermore, macrophages expressing the VEGFR-3 and VEGFR-2 ligand VEGF-C localized to vessel branch points, and Vegfc heterozygous mice exhibited inefficient angiogenesis characterized by decreased vascular branching. FoxC2 is a known regulator of Notch ligand and target gene expression, and Foxc2(+/-); Vegfr3(+/-) compound heterozygosity recapitulated homozygous loss of Vegfr3. These results indicate that macrophage-derived VEGF-C activates VEGFR-3 in tip cells to reinforce Notch signalling, which contributes to the phenotypic conversion of endothelial cells at fusion points of vessel sprouts.

引用

页码：1202 / 1213

页数：12

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