Ets2 determines the inflammatory state of endothelial cells in advanced atherosclerotic lesions

C.Y. Cheng, D. Tempel, W.K. den Dekker, R. Haasdijk, I. Chrifi, F.L. Bos, K. Wagtmans, E.H. van de Kamp, L. Blonden, E.A. Biessen, F.L. Moll, G. Pasterkamp, P.W. Serruys, S. Schulte-Merker, H.J. Duckers

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RATIONALE: 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. OBJECTIVES: We assessed the role of Ets2 in endothelial cells during atherosclerotic lesion progression toward plaque instability. METHODS AND 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-alpha (TNFalpha), 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 TNFalpha. 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 TNFalpha-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 TNFalpha-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. [KEYWORDS: Analysis of Variance, Animals, Aortic Diseases/immunology/ metabolism/pathology/physiopathology, Apolipoproteins E/deficiency/genetics, Carotid Artery Diseases/immunology/ metabolism/pathology/physiopathology, Cells, Cultured, Chemokine CCL2/metabolism, Disease Models, Animal, Endothelial Cells/immunology/ metabolism, Hemorrhage/metabolism, Humans, Inflammation/immunology/ metabolism/pathology/physiopathology, Inflammation Mediators/metabolism, Interleukin-6/metabolism, Mice, Mice, In
Originele taal-2Engels
Pagina's (van-tot)382-395
TijdschriftCirculation Research
Nummer van het tijdschrift4
StatusGepubliceerd - 2011


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