Abstract 5611: ETS2 Contributes to a Pro-atherogenic Endothelial Cell Phenotype, Causing Plaque Destabilization in Advanced Atherosclerotic Lesions
Neovascularization is a requirement for embryonic development and plays an important role in the pathogenesis of various diseases in adults. In atherosclerosis, the role of neovascularization remains to be elucidated. Previously, we conducted a genome-wide microarray analysis for vasculogenesis during murine embryonic development. The E26 Transformation-specific Sequence 2 (ETS2) transcription factor was upregulated in Flk1+ angioblasts and vascular expression of ETS2 was validated by whole mount in situ hybridization in the developing zebrafish. We sought to assess the role of ETS2 on neovascularization during atherosclerotic lesion progression toward plaque instability. We conducted experiments in ApoE−/− mice using a vulnerable plaque (VP) model that creates vulnerable and stable plaques in the common carotid artery by flow alteration. QPCR analysis showed that ETS2 expression is augmented in vulnerable versus stable lesions (P<0,05, N=3). Stimulation with the pro-atherogenic cytokine TNFα increased ETS2 expression and induced ETS2 translocation from the golgi area to the nucleus. Western Diet increased ETS2 expression on the endothelium of the aorta of ApoE−/− animals compared with chow-fed controls, indicated by whole mount staining (P<0,05, N=4). In vitro knockdown of ETS2 by SiRNA in HUVECs diminished the expression of the cytokines MCP1, IL6, and the adhesion molecule VCAM1, under basal conditions and in response to TNFα (P<0,05, N=4). ETS2 knockdown by SiRNA impeded new vessel formation in a matrigel tube-formation assay (P<0,05, N=8). In vivo, adenoviral transduction of ETS2 in the adventitia of the VP region significantly augmented the vascular network of the adventitia compared with shamvirus treated controls. ETS2 overexpression increased both lesion size and necrotic core area, and promoted plaque destabilization by increasing intraplaque lipid and macrophage accumulation, while vascular smooth muscle cell accumulation was diminished. In conclusion, ETS2 expression correlates with plaque instability and responds to pro-atherogenic stimuli. Subsequently, ETS2 function is crucial for induction of the pro-atherogenic EC phenotype and promotes destabilization in advanced atherosclerotic lesions.