© 2000 American Heart Association, Inc.
Molecular Medicine |
Angiopoietin-1 Regulates Endothelial Cell Survival Through the Phosphatidylinositol 3'-Kinase/Akt Signal Transduction Pathway
From the National Creative Research Initiatives Center for Cardiac Regeneration and Institute of Cardiovascular Research (I.K., H.G.K., H.J.K., G.Y.K.), Department of Pathology (J.H.K.), Chonbuk National University School of Medicine, and Department of Biotechnology (J.-N.S.), Woosuk University, Chonju, Korea.
Correspondence to Gou Young Koh, MD, PhD, National Creative Research Initiatives Center for Cardiac Regeneration, Chonbuk National University School of Medicine, San 2-20, Keum-Am-Dong, Chonju, 560-180, Republic of Korea. E-mail gykoh{at}moak.chonbuk.ac.kr
Abstract—Angiopoietin-1 (Ang1) is a strong apoptosis survival factor for endothelial cells. In this study, the receptor/second messenger signal transduction pathway for the antiapoptotic effect of Ang1 on human umbilical vein endothelial cells was examined. Pretreatment with soluble Tie2 receptor, but not Tie1 receptor, blocked the Ang1-induced antiapoptotic effect. Ang1 induced phosphorylation of Tie2 and the p85 subunit of phosphatidylinositol 3'-kinase (PI 3'-kinase) and increased PI 3'-kinase activity in a dose-dependent manner. The PI 3'-kinase–specific inhibitors wortmannin and LY294002 blocked the Ang1-induced antiapoptotic effect. Ang1 induced phosphorylation of the serine-threonine kinase Akt at Ser473 in a PI 3'-kinase–dependent manner. Expression of a dominant-negative form of Akt reversed the Ang1-induced antiapoptotic effect. Ang1 mRNA and protein were present in vascular smooth muscle cells but not in endothelial cells. Cultured vascular smooth muscle cells, but not human umbilical vein endothelial cells, secreted Ang1. These findings indicate that the Tie2 receptor, PI 3'-kinase, and Akt are crucial elements in the signal transduction pathway leading to endothelial cell survival induced by the paracrine activity of Ang1.
Key Words: angiopoietin-1 • endothelial cell • apoptosis
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 O. Feraud, C. Mallet, and I. Vilgrain Expressional Regulation of the Angiopoietin-1 and -2 and the Endothelial-Specific Receptor Tyrosine Kinase Tie2 in Adrenal Atrophy: A Study of Adrenocorticotropin-Induced Repair Endocrinology, October 1, 2003; 144(10): 4607 - 4615. [Abstract] [Full Text] [PDF]
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R. Schafer, D. Abraham, P. Paulus, R. Blumer, M. Grimm, J. Wojta, and S. Aharinejad Impaired VE-Cadherin/{beta}-Catenin Expression Mediates Endothelial Cell Degeneration in Dilated Cardiomyopathy Circulation, September 30, 2003; 108(13): 1585 - 1591. [Abstract] [Full Text] [PDF]
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 V. Chhokar and A. L. Tucker Angiogenesis: Basic Mechanisms and Clinical Applications Seminars in Cardiothoracic and Vascular Anesthesia, September 1, 2003; 7(3): 253 - 280. [Abstract] [PDF]
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Z. Master, J. Tran, A. Bishnoi, S. H. Chen, J. M. L. Ebos, P. Van Slyke, R. S. Kerbel, and D. J. Dumont Dok-R Binds c-Abl and Regulates Abl Kinase Activity and Mediates Cytoskeletal Reorganization J. Biol. Chem., August 8, 2003; 278(32): 30170 - 30179. [Abstract] [Full Text] [PDF]
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S. Babaei, K. Teichert-Kuliszewska, Q. Zhang, N. Jones, D. J. Dumont, and D. J. Stewart Angiogenic Actions of Angiopoietin-1 Require Endothelium-Derived Nitric Oxide Am. J. Pathol., June 1, 2003; 162(6): 1927 - 1936. [Abstract] [Full Text] [PDF]
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Y. D. Zhao, A. I.M. Campbell, M. Robb, D. Ng, and D. J. Stewart Protective Role of Angiopoietin-1 in Experimental Pulmonary Hypertension Circ. Res., May 16, 2003; 92(9): 984 - 991. [Abstract] [Full Text] [PDF]
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W.-H. Zhu, A. MacIntyre, and R. F. Nicosia Regulation of Angiogenesis by Vascular Endothelial Growth Factor and Angiopoietin-1 in the Rat Aorta Model : Distinct Temporal Patterns of Intracellular Signaling Correlate with Induction of Angiogenic Sprouting Am. J. Pathol., September 1, 2002; 161(3): 823 - 830. [Abstract] [Full Text] [PDF]
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M. Sata and R. Nagai Phosphatidylinositol 3-Kinase: A Key Regulator of Vascular Tone? Circ. Res., August 23, 2002; 91(4): 273 - 275. [Full Text] [PDF]
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X.-L. Niu, K. G. Peters, and C. D. Kontos Deletion of the Carboxyl Terminus of Tie2 Enhances Kinase Activity, Signaling, and Function. EVIDENCE FOR AN AUTOINHIBITORY MECHANISM J. Biol. Chem., August 23, 2002; 277(35): 31768 - 31773. [Abstract] [Full Text] [PDF]
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I. Shiojima and K. Walsh Role of Akt Signaling in Vascular Homeostasis and Angiogenesis Circ. Res., June 28, 2002; 90(12): 1243 - 1250. [Abstract] [Full Text] [PDF]
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E. Chavakis and S. Dimmeler Regulation of Endothelial Cell Survival and Apoptosis During Angiogenesis Arterioscler Thromb Vasc Biol, June 1, 2002; 22(6): 887 - 893. [Abstract] [Full Text] [PDF]
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A. M. Joussen, V. Poulaki, A. Tsujikawa, W. Qin, T. Qaum, Q. Xu, Y. Moromizato, S.-E. Bursell, S. J. Wiegand, J. Rudge, et al. Suppression of Diabetic Retinopathy with Angiopoietin-1 Am. J. Pathol., May 1, 2002; 160(5): 1683 - 1693. [Abstract] [Full Text] [PDF]
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J. Tran, Z. Master, J. L. Yu, J. Rak, D. J. Dumont, and R. S. Kerbel A role for survivin in chemoresistance of endothelial cells mediated by VEGF PNAS, April 2, 2002; 99(7): 4349 - 4354. [Abstract] [Full Text] [PDF]
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 C. D. Kontos, E. H. Cha, J. D. York, and K. G. Peters The Endothelial Receptor Tyrosine Kinase Tie1 Activates Phosphatidylinositol 3-Kinase and Akt To Inhibit Apoptosis Mol. Cell. Biol., March 15, 2002; 22(6): 1704 - 1713. [Abstract] [Full Text] [PDF]
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P. Hewett, S. Nijjar, M. Shams, S. Morgan, J. Gupta, and A. Ahmed Down-Regulation of Angiopoietin-1 Expression in Menorrhagia Am. J. Pathol., March 1, 2002; 160(3): 773 - 780. [Abstract] [Full Text] [PDF]
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 S.M. DALLABRIDA and M.A. RUPNICK Vascular Endothelium in Tissue Remodeling: Implications for Heart Failure Cold Spring Harb Symp Quant Biol, January 1, 2002; 67(0): 417 - 428. [Abstract] [PDF]
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 E. A. Lidington, R. M. Rao, F. M. Marelli-Berg, P. S. Jat, D. O. Haskard, and J. C. Mason Conditional immortalization of growth factor-responsive cardiac endothelial cells from H-2Kb-tsA58 mice Am J Physiol Cell Physiol, January 1, 2002; 282(1): C67 - C74. [Abstract] [Full Text] [PDF]
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 D. M. MCDONALD Angiogenesis and Remodeling of Airway Vasculature in Chronic Inflammation Am. J. Respir. Crit. Care Med., November 15, 2001; 164(10): S39 - 45. [Abstract] [Full Text] [PDF]
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 K. Abdulmalek, F. Ashur, N. Ezer, F. Ye, S. Magder, and S. N. A. Hussain Differential expression of Tie-2 receptors and angiopoietins in response to in vivo hypoxia in rats Am J Physiol Lung Cell Mol Physiol, September 1, 2001; 281(3): L582 - L590. [Abstract] [Full Text] [PDF]
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L. Rossig, A. S. Jadidi, C. Urbich, C. Badorff, A. M. Zeiher, and S. Dimmeler Akt-Dependent Phosphorylation of p21Cip1 Regulates PCNA Binding and Proliferation of Endothelial Cells Mol. Cell. Biol., August 15, 2001; 21(16): 5644 - 5657. [Abstract] [Full Text] [PDF]
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 I. Kim, S.-O. Moon, C.-Y. Han, Y. K. Pak, S. K. Moon, J. J. Kim, and G. Y. Koh The angiopoietin-tie2 system in coronary artery endothelium prevents oxidized low-density lipoprotein-induced apoptosis Cardiovasc Res, March 1, 2001; 49(4): 872 - 881. [Abstract] [Full Text] [PDF]
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K. Teichert-Kuliszewska, P. C. Maisonpierre, N. Jones, A. I.M. Campbell, Z. Master, M. P. Bendeck, K. Alitalo, D. J. Dumont, G. D. Yancopoulos, and D. J. Stewart Biological action of angiopoietin-2 in a fibrin matrix model of angiogenesis is associated with activation of Tie2 Cardiovasc Res, February 16, 2001; 49(3): 659 - 670. [Abstract] [Full Text] [PDF]
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F. Aoudjit and K. Vuori Matrix Attachment Regulates FAS-Induced Apoptosis in Endothelial Cells: A Role for C-Flip and Implications for Anoikis J. Cell Biol., February 5, 2001; 152(3): 633 - 644. [Abstract] [Full Text] [PDF]
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T. KORFF, S. KIMMINA, G. MARTINY-BARON, and H. G. AUGUSTIN Blood vessel maturation in a 3-dimensional spheroidal coculture model: direct contact with smooth muscle cells regulates endothelial cell quiescence and abrogates VEGF responsiveness FASEB J, February 1, 2001; 15(2): 447 - 457. [Abstract] [Full Text] [PDF]
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Q. Yu and I. Stamenkovic Angiopoietin-2 Is Implicated in the Regulation of Tumor Angiogenesis Am. J. Pathol., February 1, 2001; 158(2): 563 - 570. [Abstract] [Full Text] [PDF]
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J. K. Chae, I. Kim, S. T. Lim, M. J. Chung, W. H. Kim, H. G. Kim, J. K. Ko, and G. Y. Koh Coadministration of Angiopoietin-1 and Vascular Endothelial Growth Factor Enhances Collateral Vascularization Arterioscler Thromb Vasc Biol, December 1, 2000; 20(12): 2573 - 2578. [Abstract] [Full Text] [PDF]
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S. A. Fisher, B. L. Langille, and D. Srivastava Apoptosis During Cardiovascular Development Circ. Res., November 10, 2000; 87(10): 856 - 864. [Abstract] [Full Text] [PDF]
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J. R. Gamble, J. Drew, L. Trezise, A. Underwood, M. Parsons, L. Kasminkas, J. Rudge, G. Yancopoulos, and M. A. Vadas Angiopoietin-1 Is an Antipermeability and Anti-Inflammatory Agent In Vitro and Targets Cell Junctions Circ. Res., September 29, 2000; 87(7): 603 - 607. [Abstract] [Full Text] [PDF]
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S. Dimmeler and A. M. Zeiher Endothelial Cell Apoptosis in Angiogenesis and Vessel Regression Circ. Res., September 15, 2000; 87(6): 434 - 439. [Abstract] [Full Text] [PDF]
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I. Kim, H. G. Kim, S.-O. Moon, S. W. Chae, J.-N. So, K. N. Koh, B. C. Ahn, and G. Y. Koh Angiopoietin-1 Induces Endothelial Cell Sprouting Through the Activation of Focal Adhesion Kinase and Plasmin Secretion Circ. Res., May 12, 2000; 86(9): 952 - 959. [Abstract] [Full Text] [PDF]
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S. Dimmeler and A. M. Zeiher Akt Takes Center Stage in Angiogenesis Signaling Circ. Res., January 7, 2000; 86(1): 4 - 5. [Full Text] [PDF]
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T. R. Carlson, Y. Feng, P. C. Maisonpierre, M. Mrksich, and A. O. Morla Direct Cell Adhesion to the Angiopoietins Mediated by Integrins J. Biol. Chem., July 6, 2001; 276(28): 26516 - 26525. [Abstract] [Full Text] [PDF]
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Y. Xu and Q. Yu Angiopoietin-1, Unlike Angiopoietin-2, Is Incorporated into the Extracellular Matrix via Its Linker Peptide Region J. Biol. Chem., September 7, 2001; 276(37): 34990 - 34998. [Abstract] [Full Text] [PDF]
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