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

Ulrike Fiedler^1, 7, Yvonne Reiss^1, 7, Marion Scharpfenecker^1, 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

¹  Department of Vascular Biology and Angiogenesis Research, Tumor Biology Center, Freiburg 79106, Germany.

²  Regeneron Pharmaceuticals, 777 Old Saw Mill Road, Tarrytown, New York 10591, USA.

³  Department of Internal Medicine/Infectious Diseases, Charite, Humboldt University, Berlin 13353, Germany.

⁴  Department of Medical Microbiology and Hygiene, University of Saarland Hospital, Homburg 66421, Germany.

⁵  Department of Biochemistry, University of Giessen 35392, Germany.

⁶  Department of Neurosurgery, University Clinic Mannheim, University of Heidelberg, Heidelberg 68167, Germany.

⁷  These authors contributed equally to this work.

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^{3, 4}. In turn, the antagonistic ligand Ang-2 acts by an autocrine mechanism^{5, 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-–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- and modulating TNF-–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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