title: Angiopoietin-2 functions as an autocrine protective factor in stressed endothelial cells.
abstract: 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.
authors.affiliation: Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. christopher.daly@regeneron.com
authors.forename: Christopher
authors.initials: C
authors.lastname: Daly
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Pasnikowski
authors.forename: Elena
authors.initials: E
authors.lastname: Burova
authors.forename: Vivian
authors.initials: V
authors.lastname: Wong
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Aldrich
authors.forename: Jennifer
authors.initials: J
authors.lastname: Griffiths
authors.forename: Ella
authors.initials: E
authors.lastname: Ioffe
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Daly
authors.forename: James P
authors.initials: JP
authors.lastname: Fandl
authors.forename: Nick
authors.initials: N
authors.lastname: Papadopoulos
authors.forename: Donald M
authors.initials: DM
authors.lastname: McDonald
authors.forename: Gavin
authors.initials: G
authors.lastname: Thurston
authors.forename: George D
authors.initials: GD
authors.lastname: Yancopoulos
authors.forename: John S
authors.initials: JS
authors.lastname: Rudge
mesh_terms: D000730:Androstadienes / Q000378:metabolism; D042702:Angiopoietin-2 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D019898:Autocrine Communication; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D018384:Oxidative Stress; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D042787:Receptor, TIE-2 / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D015533:Transcriptional Activation; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D042702:Angiopoietin-2; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D047428:Protein Kinase Inhibitors; D011993:Recombinant Fusion Proteins; D019869:Phosphatidylinositol 3-Kinases; D042787:Receptor, TIE-2; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin