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

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.

G‐CSF rescues tumor growth and neo‐angiogenesis during liver metastasis under host angiopoietin‐2 deficiency

“…8) were matched with C57BL/6 mice as controls. All experiments were performed in accordance with UK Animals (Scientific Procedures) Act 1986 as approved by the Local Ethical Review Process for University of Oxford or in accordance with the Regierungspr€ asidium Karlsruhe (Germany) for German Cancer Research Center, Heidelberg.…”

The Role of Angiopoietin 2 in Hyperoxia-Inuduced Acute Lung Injury

“…54 Recent reports have shown a link between Ang2 and inflammation. 55,56 Since sepsis is characterized by vascular leakage, Ang2 has also been implicated in this condition in humans. 57,58 …”

Angiopoietin 2 concentrations in infants developing bronchopulmonary dysplasia: attenuation by dexamethasone

“…2 While the role of angiopoietin 2 (Ang2) in regulating angiogenesis and vascular integrity has been well recognized, 7,8 recent reports have implicated an important role in inflammation. [9][10][11][12] Ang2 expression is increased dramatically at the sites of endothelial activation and is induced by various cytokines. 13 The release of Ang2 resulted in rapid destabilization of the endothelium and triggered an inflammatory response.…”