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The Angiopoietin-Tie2 ligand-receptor system

Endothelial activation denotes a key event in angiogenesis and vascular inflammation that causes increased responsiveness towards various pro-angiogenic or proinflammatory stimuli. In inflammation, endothelial activation is characterized by increased expression of luminal adhesion molecules, leukocyte recruitment, and altered vasomotor tone, resulting in vascular barrier breakdown [1].

The endothelial-specific angiopoietin–Tie ligand–receptor system has recently emerged as a non-redundant regulator of endothelial activation [2,3,4]. Angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) are antagonistic ligands that bind to the extracellular domain of the Tie2 receptor, which is almost exclusively expressed by endothelial cells [5,6,7]. Binding of Ang-1 to Tie2 promotes vessel integrity, inhibits vascular leakage and suppresses inflammatory gene expression [8,9,10]. Ang-2 is stored in Weibel–Palade bodies and is rapidly secreted and induced upon stimulation, whereas Ang-1 is constitutively expressed by pericytes and vascular smooth muscle cells [11,12]. Binding of antagonistic Ang-2 completely disrupts protective Tie2 signalling in the majority of experimental studies [10,13,14,15]

The important role of the Ang-Tie system has also been demonstrated in several preclinical inflammatory models. Thus, either Ang-1 gain-of-function, or Ang-2 loss-of-function animals are protected from capillary leakage and subsequent end organ damage (i.e. lung injury, circulatory shock, tissue hypoperfusion) [10,13,14,15,16].



The Literature


      1.   Fiedler U and Augustin HG: Angiopoietins: a link between angiogenesis and inflammation. Trends Immunol 2006, (27):552-558.

      2.   Davis S, Aldrich TH, Jones PF, Acheson A, Compton DL, Jain V, Ryan TE, Bruno J, Radziejewski C, Maisonpierre PC and Yancopoulos GD: Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell 1996, (87):1161-1169.

      3.   Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, Compton D, McClain J, Aldrich TH, Papadopoulos N, Daly TJ, Davis S, Sato TN and Yancopoulos GD: Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 1997, (277):55-60.

      4.   Suri C, Jones PF, Patan S, Bartunkova S, Maisonpierre PC, Davis S, Sato TN and Yancopoulos GD: Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell 1996, (87):1171-1180.

      5.   Fiedler U, Krissl T, Koidl S, Weiss C, Koblizek T, Deutsch U, Martiny-Baron G, Marme D and Augustin HG: Angiopoietin-1 and angiopoietin-2 share the same binding domains in the Tie-2 receptor involving the first Ig-like loop and the epidermal growth factor-like repeats. J Biol Chem 2003, (278):1721-1727.

      6.   Wong AL, Haroon ZA, Werner S, Dewhirst MW, Greenberg CS and Peters KG: Tie2 expression and phosphorylation in angiogenic and quiescent adult tissues. Circ Res 1997, (81):567-574.

      7.   Yuan HT, Suri C, Landon DN, Yancopoulos GD and Woolf AS: Angiopoietin-2 is a site-specific factor in differentiation of mouse renal vasculature. J Am Soc Nephrol 2000, (11):1055-1066.

      8.   Mammoto T, Parikh SM, Mammoto A, Gallagher D, Chan B, Mostoslavsky G, Ingber DE and Sukhatme VP: Angiopoietin-1 requires p190 RhoGAP to protect against vascular leakage in vivo. J Biol Chem 2007, (282):23910-23918.

      9.   Papapetropoulos A, Fulton D, Mahboubi K, Kalb RG, O'Connor DS, Li F, Altieri DC and Sessa WC: Angiopoietin-1 inhibits endothelial cell apoptosis via the Akt/survivin pathway. J Biol Chem 2000, (275):9102-9105.

     10.   Witzenbichler B, Westermann D, Knueppel S, Schultheiss HP and Tschope C: Protective role of angiopoietin-1 in endotoxic shock. Circulation 2005, (111):97-105.

     11.   Fiedler U, Scharpfenecker M, Koidl S, Hegen A, Grunow V, Schmidt JM, Kriz W, Thurston G and Augustin HG: The Tie-2 ligand angiopoietin-2 is stored in and rapidly released upon stimulation from endothelial cell Weibel-Palade bodies. Blood 2004, (103):4150-4156.

     12.   Wakui S, Yokoo K, Muto T, Suzuki Y, Takahashi H, Furusato M, Hano H, Endou H and Kanai Y: Localization of Ang-1, -2, Tie-2, and VEGF expression at endothelial-pericyte interdigitation in rat angiogenesis. Lab Invest 2006, (86):1172-1184.

     13.   McCarter SD, Mei SH, Lai PF, Zhang QW, Parker CH, Suen RS, Hood RD, Zhao YD, Deng Y, Han RN, Dumont DJ and Stewart DJ: Cell-based angiopoietin-1 gene therapy for acute lung injury. Am J Respir Crit Care Med 2007, (175):1014-1026.

     14.   Thurston G, Suri C, Smith K, McClain J, Sato TN, Yancopoulos GD and McDonald DM: Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-1. Science 1999, (286):2511-2514.

     15.   Thurston G, Rudge JS, Ioffe E, Zhou H, Ross L, Croll SD, Glazer N, Holash J, McDonald DM and Yancopoulos GD: Angiopoietin-1 protects the adult vasculature against plasma leakage. Nat Med 2000, (6):460-463.

     16.   Fiedler U, Reiss Y, Scharpfenecker M, Grunow V, Koidl S, Thurston G, Gale NW, Witzenrath M, Rosseau S, Suttorp N, Sobke A, Herrmann M, Preissner KT, Vajkoczy P and Augustin HG: Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation. Nat Med 2006, (12):235-239.

     17.   Lukasz A, Hellpap J, Horn R, Kielstein JT, David S, Haller H and Kumpers P: Circulating angiopoietin-1 and angiopoietin-2 in critically ill patients: development and clinical application of two new immunoassays. Crit Care 2008, (12):R94.

     18.   Kumpers P, Koenecke C, Hecker H, Hellpap J, Horn R, Verhagen W, Buchholz S, Hertenstein B, Krauter J, Eder M, David S, Gohring G, Haller H and Ganser A: Angiopoietin-2 predicts disease-free survival after allogeneic stem-cell transplantation in patients with high-risk myeloid malignancies. Blood 2008.