title: Reduced pathological angiogenesis and tumor growth in mice lacking GPR4, a proton sensing receptor.
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.
authors: Novartis Institutes for Biomedical Research, Forum 1 Novartis Campus, CH-4056, Basel, Switzerland.
authors: Lorenza
authors: L
authors: Wyder
authors: Thomas
authors: T
authors: Suply
authors: Bérangère
authors: B
authors: Ricoux
authors: Eric
authors: E
authors: Billy
authors: Christian
authors: C
authors: Schnell
authors: Birgit U
authors: BU
authors: Baumgarten
authors: Sauveur Michel
authors: SM
authors: Maira
authors: Claudia
authors: C
authors: Koelbing
authors: Mireille
authors: M
authors: Ferretti
authors: Bernd
authors: B
authors: Kinzel
authors: Matthias
authors: M
authors: Müller
authors: Klaus
authors: K
authors: Seuwen
authors: Marie-Gabrielle
authors: MG
authors: Ludwig
mesh_terms: D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D019295:Computational Biology; D017931:DNA Primers / Q000235:genetics; D004591:Electrophoresis, Polyacrylamide Gel; D042783:Endothelial Cells / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009369:Neoplasms / Q000378:metabolism / Q000503:physiopathology*; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D017931:DNA Primers; C517811:GPR4 protein, mouse; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D040301:Vascular Endothelial Growth Factor Receptor-2