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Letter

Nature Medicine 12, 235 - 239 (2006)
Published online: 5 February 2006 | doi:10.1038/nm1351

Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation

Ulrike Fiedler1,7, Yvonne Reiss1,7, Marion Scharpfenecker1,7, Verena Grunow1, Stefanie Koidl1, Gavin Thurston2, Nicholas W Gale2, Martin Witzenrath3, Simone Rosseau3, Norbert Suttorp3, Astrid Sobke4, Matthias Herrmann4, Klaus T Preissner5, Peter Vajkoczy6 & Hellmut G Augustin1

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 quiescence3, 4. In turn, the antagonistic ligand Ang-2 acts by an autocrine mechanism5, 6, 7 and is stored in endothelial Weibel-Palade bodies from where it can be rapidly released upon stimulation8. 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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