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


  • T. Tammela
  • G. Zarkada
  • H. Nurmi
  • L. Jakobsson
  • K. Heinolainen
  • D. Tvorogov
  • W. Zheng
  • C.A. Franco
  • A. Murtomäki
  • E. Aranda
  • N. Miura
  • S. Ylä-Herttuala
  • M. Fruttiger
  • T. Mäkinen
  • A. Eichmann
  • J.W. Pollard
  • H. Gerhardt
  • K. Alitalo


  • Nature Cell Biology


  • Nat Cell Biol 13 (10): 1202-1213


  • 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.