Angiopoietin-2 differentially regulates angiogenesis through TIE2 and integrin signaling

作者：Felcht, Moritz; Luck, Robert; Schering, Alexander; Seidel, Philipp; Srivastava, Kshitij; Hu, Junhao; Bartol, Arne; Kienast, Yvonne; Vettel, Christiane; Loos, Elias K.; Kutschera, Simone; Bartels, Susanne; Appak, Sila; Besemfelder, Eva; Terhardt, Dorothee; Chavakis, Emmanouil; Wieland, Thomas; Klein, Christian; Thomas, Markus; Uemura, Akiyoshi; Goerdt, Sergij; Augustin, Hellmut G.^*

来源：Journal of Clinical Investigation, 2012, 122(6): 1991-2005.

DOI：10.1172/JCI58832

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

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.

• 出版日期2012-6