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JCS ePress
online publication date 1 Feb 2005
doi: 10.1242/jcs.01653
Research Article
The Tie-2 ligand Angiopoietin-2 destabilizes quiescent endothelium through an internal autocrine loop mechanism
Marion Scharpfenecker,
Ulrike Fiedler,
Yvonne Reiss,
and
Hellmut G. Augustin*
* Author for correspondence (e-mail: augustin{at}angiogenese.de)
The angiopoietins Ang-1 and Ang-2 have been identified as ligands of the endothelial receptor tyrosine kinase Tie-2, which controls vascular assembly and endothelial quiescence. The largely complementary phenotypes of Ang-1-deficient mice and Ang-2-overexpressing mice have led to an antagonistic model in which Ang-1 acts as Tie-2-activating agonist and Ang-2 acts as a Tie-2-inhibiting antagonist. To date, no mechanistic equivalent of the antagonistic Ang-1/Ang-2 model has been established and the mechanisms of Ang-2 function in particular remain mysterious. We have studied the effector functions of Ang-1 and Ang-2 on quiescent endothelial cells using a three-dimensional co-culture model of endothelial cells and smooth-muscle cells. Endothelial-cell monolayer integrity in this model is dependent on Tie-2 signaling, as evidenced by detaching endothelial cells following exposure to the small molecular weight Tie-2 inhibitor A-422885.66, which cannot be overcome by exogenous Ang-1. Accordingly, exogenous Ang-2 rapidly destabilizes the endothelial layer, which can be observed within 30-60 minutes and leads to prominent endothelial-cell detachment within 4 hours. Exogenous Ang-2-mediated endothelial-cell detachment can be rescued by Ang-1, soluble Tie-2 and vascular endothelial growth factor. Similar findings were obtained in an umbilical-vein explant model. Ang-2 is mainly produced by endothelial cells and therefore acts primarily in an autocrine manner. Thus, stimulated release of endogenous Ang-2 or overexpression of Ang-2 in endothelial cells perturbs co-culture spheroid integrity, which can be rescued by exogenous Ang-1 and vascular endothelial growth factor. However, autocrine Ang-2-mediated endothelial-cell detachment cannot be blocked by soluble Tie-2. Taken together, the data demonstrate for the first time the antagonistic Ang-1/Ang-2 concept in a defined cellular model and identify Ang-2 as a rapidly acting autocrine regulator of the endothelium that acts through an internal autocrine loop mechanism.
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|
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|
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|
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|
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|
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|
|
|
|
|
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|
K. Anargyrou, E. Terpos, T. P. Vassilakopoulos, A. Pouli, S. Sachanas, T. Tzenou, S. Masouridis, D. Christoulas, M. K. Angelopoulou, E. M. Dimitriadou, et al.
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|
|
|
|
|
|
|
Y. Lan, B. Liu, H. Yao, F. Li, T. Weng, G. Yang, W. Li, X. Cheng, N. Mao, and X. Yang
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27(21):
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|
|
|
|
|
|
|
D. Liu, J. Wang, B. Kinzel, M. Mueller, X. Mao, R. Valdez, Y. Liu, and E. Li
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110(5):
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|
|
|
|
|
|
|
M. P. de Caestecker
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[PDF]
|
|
|
|
|
|
|
B. Dome, M. J.C. Hendrix, S. Paku, J. Tovari, and J. Timar
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January 1, 2007;
170(1):
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[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Daly, E. Pasnikowski, E. Burova, V. Wong, T. H. Aldrich, J. Griffiths, E. Ioffe, T. J. Daly, J. P. Fandl, N. Papadopoulos, et al.
Angiopoietin-2 functions as an autocrine protective factor in stressed endothelial cells
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October 17, 2006;
103(42):
15491 - 15496.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Pfaff, U. Fiedler, and H. G. Augustin
Emerging roles of the Angiopoietin-Tie and the ephrin-Eph systems as regulators of cell trafficking
J. Leukoc. Biol.,
October 1, 2006;
80(4):
719 - 726.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. Kalomenidis, A. Kollintza, I. Sigala, A. Papapetropoulos, S. Papiris, R. W. Light, and C. Roussos
Angiopoietin-2 Levels Are Elevated in Exudative Pleural Effusions
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May 1, 2006;
129(5):
1259 - 1266.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. P.J. Brindle, P. Saharinen, and K. Alitalo
Signaling and Functions of Angiopoietin-1 in Vascular Protection
Circ. Res.,
April 28, 2006;
98(8):
1014 - 1023.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. D. Phelps, D. L. Updike, E. C. Bullen, P. Grammas, and E. W. Howard
Transcriptional and posttranscriptional regulation of angiopoietin-2 expression mediated by IGF and PDGF in vascular smooth muscle cells
Am J Physiol Cell Physiol,
February 1, 2006;
290(2):
C352 - C361.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. E. Fathers, C. M. Stone, K. Minhas, J. J.A. Marriott, J. D. Greenwood, D. J. Dumont, and B. L. Coomber
Heterogeneity of Tie2 Expression in Tumor Microcirculation: Influence of Cancer Type, Implantation Site, and Response to Therapy
Am. J. Pathol.,
December 1, 2005;
167(6):
1753 - 1762.
[Abstract]
[Full Text]
[PDF]
|
|
|
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