GPR4 plays a critical role in endothelial cell function and mediates the effects of sphingosylphosphorylcholine.
Angiogenesis is critical for many physiological and pathological processes. We show here that the lipid sphingosylphosphorylcholine (SPC) induces angiogenesis in vivo and GPR4 is required for the biological effects of SPC on endothelial cells (EC). In human umbilical vein EC, down-regulation of GPR4 specifically inhibits SPC-, but not sphingosine-1-phosphate-, or vascular endothelial growth factor (VEGF)-induced tube formation. Re-introduction of GPR4 fully restores the activity of SPC. In microvascular EC, GPR4 plays a pivotal role in cell survival, growth, migration, and tube formation through both SPC-dependent and -independent pathways. The biological effects resulting from SPC/GPR4 interactions involve the activation of both phosphatidylinositol-3 kinase and Akt. Moreover, the effects of SPC on EC require SPC induced trans-phosphorylation and activation of the VEGF receptor 2. These results identify SPC and its receptor, GPR4, as critical regulators of the angiogenic potential of EC.
Kim
Kwan-Sik
KS
Department of Cancer Biology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Ren
Juan
J
Jiang
Ying
Y
Ebrahem
Quteba
Q
Tipps
Russell
R
Cristina
Kelly
K
Xiao
Yi-jin
YJ
Qiao
Jing
J
Taylor
Kevin L
KL
Lum
Hazel
H
Anand-Apte
Bela
B
Xu
Yan
Y
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002455:Cell Division / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D002642:Chick Embryo; D042783:Endothelial Cells / Q000502:physiology*; D004789:Enzyme Activation; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008246:Lysophospholipids / Q000494:pharmacology; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010446:Peptide Fragments / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000502:physiology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014471:Umbilical Veins; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
D000906:Antibodies; C091670:GPR4 protein, human; D008246:Lysophospholipids; D010446:Peptide Fragments; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; D042461:Vascular Endothelial Growth Factor A; C005356:sphingosine phosphorylcholine; D010767:Phosphorylcholine; C060506:sphingosine 1-phosphate; D019869:Phosphatidylinositol 3-Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D051058:Oncogene Protein v-akt; D013110:Sphingosine