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Title: VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling
Authors: Tammela, Tuomas ×
Zarkada, Georgia
Nurmi, Harri
Jakobsson, Lars
Heinolainen, Krista
Tvorogov, Denis
Zheng, Wei
Franco, Claudio A
Murtomäki, Aino
Aranda, Evelyn
Miura, Naoyuki
Ylä-Herttuala, Seppo
Fruttiger, Marcus
Mäkinen, Taija
Eichmann, Anne
Pollard, Jeffrey W
Gerhardt, Holger
Alitalo, Kari #
Issue Date: Oct-2011
Publisher: Macmillan Magazines Ltd.
Series Title: Nature Cell Biology vol:13 issue:10 pages:1202-13
Article number: 10.1038/ncb2331
Abstract: 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.
URI: 
ISSN: 1465-7392
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Vascular Patterning Laboratory (Vesalius Research Center) (+)
× corresponding author
# (joint) last author

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