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

Tuomas Tammela, Georgia Zarkada, Harri Nurmi, Lars Jakobsson, Krista Heinolainen, Denis Tvorogov, Wei Zheng, Claudio A. Franco, Aino Murtomäki, Evelyn Aranda, Naoyuki Miura, Seppo Ylä-Herttuala, Marcus Fruttiger, Taija Mäkinen, Anne Eichmann, Jeffrey W. Pollard, Holger Gerhardt, Kari Alitalo

Research output: Contribution to journalArticle

203 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1202-1213
Number of pages12
JournalNature Cell Biology
Volume13
Issue number10
DOIs
StatePublished - Oct 2011

ASJC Scopus subject areas

  • Cell Biology

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    Tammela, T., Zarkada, G., Nurmi, H., Jakobsson, L., Heinolainen, K., Tvorogov, D., Zheng, W., Franco, C. A., Murtomäki, A., Aranda, E., Miura, N., Ylä-Herttuala, S., Fruttiger, M., Mäkinen, T., Eichmann, A., Pollard, J. W., Gerhardt, H., & Alitalo, K. (2011). VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling. Nature Cell Biology, 13(10), 1202-1213. https://doi.org/10.1038/ncb2331