Angiopoietin-2 differentially regulates angiogenesis through TIE2 and integrin signaling

被引：401

作者：

Felcht, Moritz ^{[2
,3
]}

Luck, Robert ^{[2
]}

Schering, Alexander ^{[2
]}

Seidel, Philipp ^{[2
]}

Srivastava, Kshitij ^{[2
]}

Hu, Junhao ^{[2
]}

Bartol, Arne ^{[1
,2
]}

Kienast, Yvonne ^{[5
]}

Vettel, Christiane ^{[4
]}

Loos, Elias K. ^{[2
]}

Kutschera, Simone ^{[1
,2
]}

Bartels, Susanne ^{[2
]}

Appak, Sila ^{[1
,2
]}

Besemfelder, Eva ^{[2
]}

Terhardt, Dorothee ^{[2
]}

Chavakis, Emmanouil ^{[6
,7
]}

Wieland, Thomas ^{[4
]}

Klein, Christian ^{[5
]}

Thomas, Markus ^{[5
]}

Uemura, Akiyoshi ^{[8
]}

Goerdt, Sergij ^{[3
]}

Augustin, Hellmut G. ^{[1
,2
]}

机构：

[1] Heidelberg Univ, Med Fac Mannheim, Dept Vasc Biol & Tumor Angiogenesis CBTM, D-6800 Mannheim, Germany

[2] DKFZ ZMBH Alliance, German Canc Res Ctr Heidelberg, Div Vasc Oncol & Metastasis, Mannheim, Germany

[3] Heidelberg Univ, Med Fac Mannheim, Dept Dermatol Venerol & Allergol, D-6800 Mannheim, Germany

[4] Heidelberg Univ, Med Fac Mannheim, Inst Expt & Clin Pharmacol & Toxicol, D-6800 Mannheim, Germany

[5] Roche Diagnost GmbH, Penzberg, Germany

[6] Goethe Univ Frankfurt, Dept Internal Med, Ctr Mol Med, Frankfurt, Germany

[7] Goethe Univ Frankfurt, Inst Cardiovasc Regenerat, Ctr Mol Med, Frankfurt, Germany

[8] Kobe Univ, Grad Sch Med, Dept Physiol & Cell Biol, Div Vasc Biol, Kobe, Hyogo 657, Japan

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2012年 / 122卷 / 06期

关键词：

ENDOTHELIAL-CELLS; VESSEL MATURATION; TUMOR-GROWTH; ADHESION; EXPRESSION; RECEPTOR; METASTASIS; ACTIVATION; LIGAND; STIMULATION;

D O I：

10.1172/JCI58832

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Angiopoietin-2 (ANG-2) is a key regulator of angiogenesis that exerts context-dependent effects on ECs. ANG-2 binds the endothelial-specific receptor tyrosine kinase 2 (TIE2) and acts as a negative regulator of ANG-1/TIE2 signaling during angiogenesis, thereby controlling the responsiveness of ECs to exogenous cytokines. Recent data from tumors indicate that under certain conditions ANG-2 can also promote angiogenesis. However, the molecular mechanisms of dual ANG-2 functions are poorly understood. Here, we identify a model for the opposing roles of ANG-2 in angiogenesis. We found that angiogenesis-activated endothelium harbored a subpopulation of TIE2-negative ECs (TIE2(lo)). TIE2 expression was downregulated in angiogenic ECs, which abundantly expressed several integrins. ANG-2 bound to these integrins in TIE2(lo) ECs, subsequently inducing, in a TIE2-independent manner, phosphorylation of the integrin adaptor protein FAK, resulting in RAC1 activation, migration, and sprouting angiogenesis. Correspondingly, in vivo ANG-2 blockade interfered with integrin signaling and inhibited FAK phosphorylation and sprouting angiogenesis of TIE2(lo) ECs. These data establish a contextual model whereby differential TIE2 and integrin expression, binding, and activation control the role of ANG-2 in angiogenesis. The results of this study have immediate translational implications for the therapeutic exploitation of angiopoietin signaling.

引用

页码：1991 / 2005

页数：15

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