Angiopoietin-2 functions as an autocrine protective factor in stressed endothelial cells
| Autor: | Aldrich Thomas H, Elena Burova, Jennifer A. Griffiths, John S. Rudge, Elizabeth Pasnikowski, Thomas J. Daly, Vivian Wong, James P. Fandl, Donald M. McDonald, Gavin Thurston, Nick Papadopoulos, Ella Ioffe, George D. Yancopoulos, Christopher Daly |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Transcriptional Activation
Agonist medicine.drug_class Recombinant Fusion Proteins Apoptosis Biology Autocrine Communication TIE1 Angiopoietin-2 Angiopoietin Mice Phosphatidylinositol 3-Kinases medicine Animals Humans Phosphorylation Autocrine signalling Protein Kinase Inhibitors Protein kinase B Cells Cultured PI3K/AKT/mTOR pathway Multidisciplinary Forkhead Box Protein O1 Endothelial Cells Forkhead Transcription Factors Biological Sciences Receptor TIE-2 Angiopoietin receptor Cell biology Androstadienes Oxidative Stress embryonic structures cardiovascular system Cancer research biology.protein RNA Interference Wortmannin Proto-Oncogene Proteins c-akt hormones hormone substitutes and hormone antagonists Signal Transduction |
| Zdroj: | Proceedings of the National Academy of Sciences. 103:15491-15496 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Angiopoietin (Ang)-2, a context-dependent agonist/antagonist for the vascular-specific Tie2 receptor, is highly expressed by endothelial cells at sites of normal and pathologic angiogenesis. One prevailing model suggests that in these settings, Ang-2 acts as an autocrine Tie2 blocker, inhibiting the stabilizing influence of the Tie2 activator Ang-1, thereby promoting vascular remodeling. However, the effects of endogenous Ang-2 on cells that are actively producing it have not been studied in detail. Here, we demonstrate that Ang-2 expression is rapidly induced in endothelial cells by the transcription factor FOXO1 after inhibition of the phosphatidylinositol 3-kinase/Akt pathway. We employ RNAi and blocking antibodies to show that in this setting, Ang-2 unexpectedly functions as a Tie2 agonist, bolstering Akt activity so as to provide negative feedback on FOXO1-regulated transcription and apoptosis. In addition, we show that Ang-2, like Ang-1, activates Tie2/Akt signaling in vivo , thereby inhibiting the expression of FOXO1 target genes. Consistent with a role for Ang-2 as a Tie2 activator, we demonstrate that Ang-2 inhibits vascular leak. Our data suggests a model in which Ang-2 expression is induced in stressed endothelial cells, where it acts as an autocrine Tie2 agonist and protective factor. |
| Databáze: | OpenAIRE |
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