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

Item Type:Article
Title:VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling
Creators Name:Tammela, T. and Zarkada, G. and Nurmi, H. and Jakobsson, L. and Heinolainen, K. and Tvorogov, D. and Zheng, W. and Franco, C.A. and Murtomäki, A. and Aranda, E. and Miura, N. and Ylä-Herttuala, S. and Fruttiger, M. and Mäkinen, T. and Eichmann, A. and Pollard, J.W. and Gerhardt, H. and Alitalo, K.
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.
Keywords:Antibodies, Endothelial Cells, Forkhead Transcription Factors, Gene Expression Regulation, Genetic Transduction, Human Umbilical Vein Endothelial Cells, Knockout Mice, Macrophages, Notch Receptors, Pathologic Neovascularization, Phosphatidylinositol 3-Kinase, Physiologic Neovascularization, Protein Kinase Inhibitors, RNA Interference, Retinal Vessels, Rhombencephalon, Signal Transduction, Time Factors, Transfection, Tumor Cell Line, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor B, Vascular Endothelial Growth Factor C, Vascular Endothelial Growth Factor D, Vascular Endothelial Growth Factor Receptor-3, Animals, Mice
Source:Nature Cell Biology
Publisher:Nature Publishing Group
Page Range:1202-1213
Date:11 September 2011
Official Publication:https://doi.org/10.1038/ncb2331
PubMed:View item in PubMed

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