Ets2 Determines the Inflammatory State of Endothelial Cells in Advanced Atherosclerotic Lesions

Caroline Cheng, Dennie Tempel, Wijnand K. Den Dekker, Remco A. Haasdijk, Ihsan Chrifi, Frank L. Bos, Kim Wagtmans, Esther H. M. Van De Kamp, Lau A. J. Blonden, Erik A. L. Biessen, Frans L. Moll, Gerard Pasterkamp, Patrick W. Serruys, Stefan Schulte-Merker, Henricus J. Duckers*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

35 Citations (Web of Science)

Abstract

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 (TNF alpha), 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 TNF alpha. 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 TNF alpha-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 TNF alpha-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. (Circ Res. 2011;109:382-395.)
Original languageEnglish
Pages (from-to)385-395
JournalCirculation Research
Volume109
Issue number4
DOIs
Publication statusPublished - 5 Aug 2011

Keywords

  • angiogenesis
  • atherosclerosis
  • endothelium
  • vascular inflammation
  • vulnerable plaque

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