Article

Fiedler, U. et al. Angiopoietin-2 sensitizes endothelial cells to TNF- and has a crucial role in the induction of inflammation. Nature Med. 12, 235-239

Humboldt-Universität zu Berlin, Berlín, Berlin, Germany
Nature Medicine (Impact Factor: 28.05). 03/2006; 12(2):235-9. DOI: 10.1038/nm1351
Source: PubMed

ABSTRACT The angiopoietins Ang-1 and Ang-2 have been identified as ligands of the receptor tyrosine kinase Tie-2 (refs. 1,2). Paracrine Ang-1-mediated activation of Tie-2 acts as a regulator of vessel maturation and vascular quiescence. In turn, the antagonistic ligand Ang-2 acts by an autocrine mechanism and is stored in endothelial Weibel-Palade bodies from where it can be rapidly released upon stimulation. The rapid release of Ang-2 implies functions of the angiopoietin-Tie system beyond its established role during vascular morphogenesis as a regulator of rapid vascular responses. Here we show that mice deficient in Ang-2 (encoded by the gene Angpt2) cannot elicit an inflammatory response in thioglycollate-induced or Staphylococcus aureus-induced peritonitis, or in the dorsal skinfold chamber model. Recombinant Ang-2 restores the inflammation defect in Angpt2(-/-) mice. Intravital microscopy showed normal TNF-alpha-induced leukocyte rolling in the vasculature of Angpt2(-/-)mice, but rolling cells did not firmly adhere to activated endothelium. Cellular experiments showed that Ang-2 promotes adhesion by sensitizing endothelial cells toward TNF-alpha and modulating TNF-alpha-induced expression of endothelial cell adhesion molecules. Together, these findings identify Ang-2 as an autocrine regulator of endothelial cell inflammatory responses. Ang-2 thereby acts as a switch of vascular responsiveness exerting a permissive role for the activities of proinflammatory cytokines.

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    • "Angiopoietin (Ang)-1, Ang-2, and their endothelial cell-specific tyrosine kinase receptor, Tie-2, interact with vascular endothelial growth factor (VEGF) to mediate endothelial activation [10]. Binding of the agonist Ang-1 to the Tie-2 receptor promotes vessel integrity, inhibits vascular permeability, and suppresses inflammatory response [11]. "
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    • "To validate the results obtained with the ANG2-blocking antibody, we also analyzed the initial lymphatics in Ang2 gene-deleted (À/À) mice (Gale et al. 2002; Fiedler et al. 2006). In agreement with the results of the blocking antibody experiment, the zipper-to-button junctional transformation was also reduced in the diaphragm of Ang2 "
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    • "Furthermore , extensive overlap in endothelial responses to inflammatory and angiogenic activation exists, in which activation of the NFκB-pathway upregulates the expression of matrix metalloproteinases and urokinase-type plasminogen activator (uPA) and pro-inflammatory cytokines and chemokines Cell Tissue Res contribute to new vessel formation (Sakurai and Kudo 2011; Ribatti 2012). On the other hand, TNFα can attenuate VEGFR2 activation by employing SHP-1 phosphatase (Guo et al. 2000) and interfere with Notch and Jagged signaling in angiogenesis (Sainson et al. 2008), while pro-angiogenic Angiopoietin-2 can sensitize endothelial cells to TNFα (Fiedler et al. 2006) and facilitate inflammation-related vascular remodeling (Thurston and Daly 2012). "
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