title: Angiopoietin 2 induces cell cycle arrest in endothelial cells: a possible mechanism involved in advanced plaque neovascularization.
abstract: OBJECTIVE
  To characterize the molecules and the mechanisms regulating the neoangiogenetic process in advanced atherosclerotic plaques.
  
  
  RESULTS
  Western blot and immunofluorescence analysis of atherosclerotic specimens demonstrated that unlike neovessels from early lesions that expressed vascular endothelial growth factor (VEGF) and angiopoietin1 (Angio1), vessels from advanced lesions expressed VEGF and angiopoietin 2 (Angio2). Moreover, only few neovessels from advanced lesions showed a positive immunostaining for proliferating cell nuclear antigen. Angio1-elicited and Angio2-elicited intracellular events in endothelial cells (EC) demonstrated that while Angio1 triggered Erk1/Erk2 mitogen activated protein kinases (MAPK) and Akt activation, Angio2 (50 ng/mL) induced STAT5 activation and p21waf expression and increased the fraction of cells in G1. Both Angio2-mediated events were abrogated by expressing a dominant negative STAT5 construct (DeltaSTAT5). Consistent with the expression of Angio2 in neovessels of advanced lesions a transcriptionally active STAT5 was detected. Moreover, co-immunoprecipitation experiments revealed the presence of a STAT5/Tie2 molecular complex in neointima vessels from advanced, but not from early, lesions.
  
  
  CONCLUSIONS
  In advanced lesions, the activation of the Tie2-mediated STAT5 signaling pathway may negatively regulate vessel growth.
authors.affiliation: Department of Internal Medicine, University of Torino, Torino, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Calvi
authors.forename: Patrizia
authors.initials: P
authors.lastname: Dentelli
authors.forename: Marco
authors.initials: M
authors.lastname: Pagano
authors.forename: Arturo
authors.initials: A
authors.lastname: Rosso
authors.forename: Marco
authors.initials: M
authors.lastname: Pegoraro
authors.forename: Sara
authors.initials: S
authors.lastname: Giunti
authors.forename: Giovanni
authors.initials: G
authors.lastname: Garbarino
authors.forename: Giovanni
authors.initials: G
authors.lastname: Camussi
authors.forename: Luigi
authors.initials: L
authors.lastname: Pegoraro
authors.forename: Maria Felice
authors.initials: MF
authors.lastname: Brizzi
mesh_terms: D042683:Angiopoietin-1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D042702:Angiopoietin-2 / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D001161:Arteriosclerosis / Q000473:pathology*; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology; D002340:Carotid Artery Diseases / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics; D045744:Cell Line, Tumor / Q000378:metabolism; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D003324:Coronary Artery Disease / Q000473:pathology; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D018450:Disease Progression; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000473:pathology; D016193:G1 Phase / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D046911:Macromolecular Substances; D008894:Milk Proteins / Q000235:genetics; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis / Q000235:genetics; D042787:Receptor, TIE-2 / Q000502:physiology*; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection; D017539:Tunica Intima / Q000473:pathology
chemical_list: D042683:Angiopoietin-1; D042702:Angiopoietin-2; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D046911:Macromolecular Substances; D008894:Milk Proteins; D018809:Proliferating Cell Nuclear Antigen; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D042787:Receptor, TIE-2