title: Ets2 determines the inflammatory state of endothelial cells in advanced atherosclerotic lesions.
abstract: BACKGROUND
  Neovascularization is required for embryonic development and plays a central role in diseases in adults. In atherosclerosis, the role of neovascularization remains to be elucidated. In a genome-wide microarray-screen of Flk1+ angioblasts during murine embryogenesis, the v-ets erythroblastosis virus E26 oncogene homolog 2 (Ets2) transcription factor was identified as a potential angiogenic factor.
  
  
  OBJECTIVE
  We assessed the role of Ets2 in endothelial cells during atherosclerotic lesion progression toward plaque instability.
  
  
  RESULTS
  In 91 patients treated for carotid artery disease, Ets2 levels showed modest correlations with capillary growth, thrombogenicity, and rising levels of tumor necrosis factor-α (TNFα), monocyte chemoattractant protein 1, and interleukin-6 in the atherosclerotic lesions. Experiments in ApoE(-/-) mice, using a vulnerable plaque model, showed that Ets2 expression was increased under atherogenic conditions and was augmented specifically in the vulnerable versus stable lesions. In endothelial cell cultures, Ets2 expression and activation was responsive to the atherogenic cytokine TNFα. In the murine vulnerable plaque model, overexpression of Ets2 promoted lesion growth with neovessel formation, hemorrhaging, and plaque destabilization. In contrast, Ets2 silencing, using a lentiviral shRNA construct, promoted lesion stabilization. In vitro studies showed that Ets2 was crucial for TNFα-induced expression of monocyte chemoattractant protein 1, interleukin-6, and vascular cell adhesion molecule 1 in endothelial cells. In addition, Ets2 promoted tube formation and amplified TNFα-induced loss of vascular endothelial integrity. Evaluation in a murine retina model further validated the role of Ets2 in regulating vessel inflammation and endothelial leakage.
  
  
  CONCLUSIONS
  We provide the first evidence for the plaque-destabilizing role of Ets2 in atherosclerosis development by induction of an intraplaque proinflammatory phenotype in endothelial cells.
authors.affiliation: Molecular Cardiology Laboratory, Experimental Cardiology, Thoraxcenter, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Caroline
authors.initials: C
authors.lastname: Cheng
authors.forename: Dennie
authors.initials: D
authors.lastname: Tempel
authors.forename: Wijnand K
authors.initials: WK
authors.lastname: Den Dekker
authors.forename: Remco
authors.initials: R
authors.lastname: Haasdijk
authors.forename: Ihsan
authors.initials: I
authors.lastname: Chrifi
authors.forename: Frank L
authors.initials: FL
authors.lastname: Bos
authors.forename: Kim
authors.initials: K
authors.lastname: Wagtmans
authors.forename: Esther H
authors.initials: EH
authors.lastname: van de Kamp
authors.forename: Lau
authors.initials: L
authors.lastname: Blonden
authors.forename: Erik A L
authors.initials: EA
authors.lastname: Biessen
authors.forename: Frans
authors.initials: F
authors.lastname: Moll
authors.forename: Gerard
authors.initials: G
authors.lastname: Pasterkamp
authors.forename: Patrick W
authors.initials: PW
authors.lastname: Serruys
authors.forename: Stefan
authors.initials: S
authors.lastname: Schulte-Merker
authors.forename: Henricus J
authors.initials: HJ
authors.lastname: Duckers
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001018:Aortic Diseases / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D002340:Carotid Artery Diseases / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism*; D006470:Hemorrhage / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000503:physiopathology; D018919:Neovascularization, Physiologic; D010641:Phenotype; D050787:Proto-Oncogene Protein c-ets-2 / Q000235:genetics / Q000378:metabolism*; D012171:Retinal Vessels / Q000378:metabolism / Q000473:pathology; D012421:Rupture; D013997:Time Factors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; C111835:CCL2 protein, human; D018932:Chemokine CCL2; C494069:ETS2 protein, human; C494070:Ets2 protein, mouse; C508600:IL6 protein, human; D018836:Inflammation Mediators; D015850:Interleukin-6; D050787:Proto-Oncogene Protein c-ets-2; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1