title: Akt is a major angiogenic mediator downstream of the Ang1/Tie2 signaling pathway.
abstract: Tie2 and VEGF receptors (VEGFRs) are tyrosine kinases that play essential roles in angiogenesis. Activation of both receptors leads to the activation of Akt, an important mediator of cell survival and cell motility. In this study, we compared the role of Akt in Tie2-mediated versus VEGF-mediated endothelial cell (EC) survival and EC sprouting. Our data show that Akt is required and sufficient to mediate Ang1-induced EC survival in response to growth factor depletion. Blocking Akt function abolishes angiopoietin 1 (Ang1), a ligand for Tie2, mediated EC survival, and activating Akt rescues a Tie2 blockade-induced EC apoptosis. In contrast, activating Akt rescues EC apoptosis induced by a VEGF blockade, but interestingly, blocking Akt function has no effects on VEGF-induced EC survival, demonstrating that Akt is sufficient but not required for VEGF-mediated EC survival. In addition, we show that both Ang1 and VEGF induce EC sprouting in a three-dimensional collagen gel, which depends on the activation of Akt. Blocking Akt action inhibited EC sprouting induced by Ang1 or VEGF. Therefore, the data show that Akt is the primary mediator of Ang1-induced EC survival while multiple pathways are involved downstream of VEGF responsible for EC survival. However, Akt is required and sufficient to mediate the EC sprouting induced by both Ang1 and VEGF.
authors.affiliation: Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Laura M
authors.initials: LM
authors.lastname: DeBusk
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Hallahan
authors.forename: Pengnian Charles
authors.initials: PC
authors.lastname: Lin
mesh_terms: D042683:Angiopoietin-1 / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology; D001808:Blood Vessels / Q000166:cytology / Q000187:drug effects / Q000254:growth & development*; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D003094:Collagen / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000254:growth & development*; D005782:Gels / Q000494:pharmacology; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D042787:Receptor, TIE-2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D042683:Angiopoietin-1; D005782:Gels; D011518:Proto-Oncogene Proteins; D042461:Vascular Endothelial Growth Factor A; D003094:Collagen; D042787:Receptor, TIE-2; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt