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
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
收藏
页码:1991 / 2005
页数:15
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