Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation.
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.
Fiedler
Ulrike
U
Department of Vascular Biology and Angiogenesis Research, Tumor Biology Center, Freiburg 79106, Germany.
Reiss
Yvonne
Y
Scharpfenecker
Marion
M
Grunow
Verena
V
Koidl
Stefanie
S
Thurston
Gavin
G
Gale
Nicholas W
NW
Witzenrath
Martin
M
Rosseau
Simone
S
Suttorp
Norbert
N
Sobke
Astrid
A
Herrmann
Matthias
M
Preissner
Klaus T
KT
Vajkoczy
Peter
P
Augustin
Hellmut G
HG
D042683:Angiopoietin-1 / Q000502:physiology; D042702:Angiopoietin-2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D016207:Cytokines / Q000502:physiology; D004730:Endothelium, Vascular / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007249:Inflammation / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D018836:Inflammation Mediators / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009389:Neovascularization, Pathologic; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D042683:Angiopoietin-1; D042702:Angiopoietin-2; D016207:Cytokines; D018836:Inflammation Mediators; D014409:Tumor Necrosis Factor-alpha