Signaling and regulation of endothelial cell survival by angiopoietin-2.
Angiopoietins are ligands for endothelial cell-specific Tie-2 receptors. Whereas angiopoietin-1 (Ang-1) activates these receptors and promotes cell survival, migration, and sprouting, little information is available regarding how Ang-2 influences these cells. In this study, we evaluated signaling pathways and biological effects of physiological concentrations of Ang-2 in cultured human umbilical vein endothelial cells. Ang-2 at 150 and 300 ng/ml elicited a transient (reaching peak values within 15 min of exposure) increase in the phosphorylation of Tie-2 receptors, protein kinase B (Akt), ERK1/2, and p38 members of the mitogen-activated protein kinases. However, unlike Ang-1, Ang-2 significantly inhibited JNK/SAPK phosphorylation. When vascular endothelial growth factor (VEGF) was present along with Ang-2, ERK1/2 phosphorylation was inhibited, whereas augmentation of Ang-1-induced ERK1/2 phosphorylation was triggered by VEGF. Ang-2 treatment had no effect on cell migration and in vitro wound healing but significantly attenuated serum deprivation-induced apoptosis and promoted survival. These effects were completely reversed by phosphatidylinositol 3 (PI3)-kinase and ERK1/2 inhibitors but were augmented by an inhibitor of the p38 pathway. These results suggest that Ang-2 promotes endothelial cell survival through the ERK1/2 and PI3-kinase pathways and that this angiopoietin is not a strong promoter of endothelial cell migration. We also conclude that the nature of interactions in terms of ERK1/2 activation between Ang-2 and VEGF is different from that of Ang-1 and VEGF.
Harfouche
Rania
R
Rm. L3.05, Critical Care Division, Royal Victoria Hospital, 687 Pine Ave West, Montreal, Quebec, Canada.
Hussain
Sabah N A
SN
D042702:Angiopoietin-2 / Q000502:physiology*; D017209:Apoptosis / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology*; D006801:Humans; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D042764:Receptors, TIE / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
D042702:Angiopoietin-2; D042461:Vascular Endothelial Growth Factor A; D019869:Phosphatidylinositol 3-Kinases; D042764:Receptors, TIE; D051057:Proto-Oncogene Proteins c-akt; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases