Angiopoietin-2 sensitizes endothelial cells to TNF-alpha 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.
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ABSTRACT: The evaluation of signaling pathways leading to gene induction by VEGF-A and IL-1 in endothelial cells supports the importance of the NF-kappaB pathway for the IL-1-induced gene repertoire, whereas VEGF-A is a strong and preferential trigger of signals via PLC-gamma. This leads (i) via Ca(++) to the activation of calcineurin and NFAT and (ii) via PKC and the MEK/ERK MAPK pathway to the upregulation of EGR-1. Part of the VEGF-triggered gene induction depends on a cooperation of the transcription factors NFAT and EGR-1. Gene activation via PLC-gamma provides VEGF with the potency to induce a wide spectrum of genes including many also upregulated by IL-1. A gene upregulated by VEGF and IL-1 is the DSCR-1 gene, which encodes an inhibitor of calcineurin. DSCR1 is induced by NFAT or NF-kappaB and limits Ca(++) signaling in a negative feed-back loop. Similarly, NAB2, a corepressor of EGR-1, is induced by EGR-1 and limits EGR-1 effects. Adenoviral overexpression of DSCR1 or NAB2 inhibited part of VEGF-induced gene expression and reduced sprouting in angiogenesis models.Clinical hemorheology and microcirculation 02/2007; 37(1-2):57-62. · 2.22 Impact Factor
- Journal of the American Society of Nephrology 05/2006; 17(5):1207-1217. DOI:10.1681/ASN.2006030259 · 9.47 Impact Factor
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ABSTRACT: The ability of small blood vessels to undergo rapid, reversible morphological changes is essential for the adaptive response to tissue injury or local infection. A canonical feature of this response is transient hyperpermeability. However, when leakiness is profound or persistent, adverse consequences accrue to the host, including organ dysfunction and shock. A growing body of literature identifies the Tie2 receptor, a transmembrane tyrosine kinase highly enriched in the endothelium, as an important regulator of vascular barrier function in health and in disease. The principal ligands of Tie2, Angiopoietins 1 and 2, exert opposite effects on this receptor in the context of inflammation. This review will focus on recent studies that have illuminated novel aspects of the exquisitely controlled Tie2 signaling axis while proposing unanswered questions and future directions for this field of study.04/2015; 3(1-2):e957508. DOI:10.4161/21688362.2014.957508