Angiogenesis

, Volume 14, Issue 4, pp 533–544

Reduced pathological angiogenesis and tumor growth in mice lacking GPR4, a proton sensing receptor

  • Lorenza Wyder
  • Thomas Suply
  • Bérangère Ricoux
  • Eric Billy
  • Christian Schnell
  • Birgit U. Baumgarten
  • Sauveur Michel Maira
  • Claudia Koelbing
  • Mireille Ferretti
  • Bernd Kinzel
  • Matthias Müller
  • Klaus Seuwen
  • Marie-Gabrielle Ludwig
Original Paper

DOI: 10.1007/s10456-011-9238-9

Cite this article as:
Wyder, L., Suply, T., Ricoux, B. et al. Angiogenesis (2011) 14: 533. doi:10.1007/s10456-011-9238-9

Abstract

The G protein-coupled receptor GPR4 is activated by acidic pH and recent evidence indicates that it is expressed in endothelial cells. In agreement with these reports, we observe a high correlation of GPR4 mRNA expression with endothelial marker genes, and we confirm expression and acidic pH dependent function of GPR4 in primary human vascular endothelial cells. GPR4-deficient mice were generated; these are viable and fertile and show no gross abnormalities. However, these animals show a significantly reduced angiogenic response to VEGF (vascular endothelial growth factor), but not to bFGF (basic fibroblast growth factor), in a growth factor implant model. Accordingly, in two different orthotopic models, tumor growth is strongly reduced in mice lacking GPR4. Histological analysis of tumors indicates reduced tumor cell proliferation as well as altered vessel morphology, length and density. Moreover, GPR4 deficiency results in reduced VEGFR2 (VEGF Receptor 2) levels in endothelial cells, accounting, at least in part, for the observed phenotype. Our data suggest that endothelial cells sense local tissue acidosis via GPR4 and that this signal is required to generate a full angiogenic response to VEGF.

Keywords

Angiogenesis Acidosis Hypoxia Endothelium Tumor 

Supplementary material

10456_2011_9238_MOESM1_ESM.doc (1.6 mb)
Supplementary material 1 (DOC 1605 kb)

Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  • Lorenza Wyder
    • 1
    • 2
  • Thomas Suply
    • 1
  • Bérangère Ricoux
    • 1
  • Eric Billy
    • 1
  • Christian Schnell
    • 1
  • Birgit U. Baumgarten
    • 1
  • Sauveur Michel Maira
    • 1
  • Claudia Koelbing
    • 1
  • Mireille Ferretti
    • 1
  • Bernd Kinzel
    • 1
  • Matthias Müller
    • 1
  • Klaus Seuwen
    • 1
  • Marie-Gabrielle Ludwig
    • 1
  1. 1.Novartis Institutes for Biomedical ResearchBaselSwitzerland
  2. 2.Actelion Pharmaceuticals LtdAllschwilSwitzerland