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

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 microarrayscreen 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-␣ (TNF␣), 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␣. 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␣-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␣-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. Key Words: angiogenesis Ⅲ atherosclerosis Ⅲ endothelium Ⅲ vascular inflammation Ⅲ vulnerable plaque A therosclerosis is a complex disease with a strong inflammatory component, [1][2][3][4] initially triggered by endothelial dysfunction and characterized by an influx of atherogenic lipoprotein components, combined with endothelial upregulation of proinflammatory cytokines and adhesion molecules. 5 Monocyte adhesion and extravasation perpetuate the disease by further differentiation into macrophages and foam cells, ultimately driving atherosclerotic lesion growth and complexity. 6 Vulnerable plaque (VP) is an advanced form of atherosclerosis, characterized by an exuberated inflammatory response with the formation of a large necrotic core, and a rupture-prone thin fibrous cap. 7 In these VPs, microvessel formation with extravasation of erythrocytes in the vasa vasorum and intimal area has been observed. 8 -10 Although new vessel formation in advanced atherosclerosis has been associated with lesion progression and instability, 10 -12 the exact molecular mechanisms that facilitate neovascularization in atherosclerosis must be further elucidated. Conclusions:Recently, we have conducted a genome-wide screen to identify new geneti...

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