Journal Article

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

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

2011

Overview

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.

• Publisher: Nature Publishing Group
• Subject: Animals / Antibodies - pharmacology / Blood vessels / Cell Line, Tumor / Cellular signal transduction / Endothelial Cells - drug effects / Endothelial Cells - metabolism / Forkhead Transcription Factors - genetics / Forkhead Transcription Factors - metabolism / Gene Expression Regulation / Growth factor receptors / Human Umbilical Vein Endothelial Cells - metabolism / Humans / Macrophages - metabolism / Medicin och hälsovetenskap / Mice / Mice, Knockout / Neovascularization, Pathologic - genetics / Neovascularization, Pathologic - metabolism / Neovascularization, Physiologic - drug effects / Phosphatidylinositol 3-Kinase - metabolism / Physiological aspects / Protein Kinase Inhibitors - pharmacology / Receptors, Notch - antagonists & inhibitors / Receptors, Notch - metabolism / Retinal Vessels - metabolism / Rhombencephalon - blood supply / RNA Interference / Signal Transduction - drug effects / Time Factors / Transduction, Genetic / Transfection / Vascular endothelial growth factor / Vascular Endothelial Growth Factor A - genetics / Vascular Endothelial Growth Factor A - metabolism / Vascular Endothelial Growth Factor B - genetics / Vascular Endothelial Growth Factor B - metabolism / Vascular Endothelial Growth Factor C - genetics / Vascular Endothelial Growth Factor C - metabolism / Vascular Endothelial Growth Factor D - genetics / Vascular Endothelial Growth Factor D - metabolism / Vascular Endothelial Growth Factor Receptor-3 - deficiency / Vascular Endothelial Growth Factor Receptor-3 - genetics / Vascular Endothelial Growth Factor Receptor-3 - metabolism