Abstract 183: Loss of Notch1 Signaling in Endothelial Cells Suppresses Progression of Atherosclerosis

Abstract

Introduction: Notch signaling plays pivotal roles in vascular development and cardiovascular disease. Our previous studies showed that the Notch pathway is activated in luminal endothelial cells (EC) at atherosclerotic plaques and results in pro-inflammatory response and senescence of EC, implicating a potential involvement of Notch signaling in atherosclerosis. Here, we investigate the role of Notch signaling in atherosclerosis using genetic mouse model with inducible endothelial cell-specific Notch1 gene deletion on an ApoE-deficient background. Methods: A genetically engineered mouse model, Notch1 FLOX/FLOX /VE-cadherin-CreER T2 /ApoE -/- , which is a Tamoxifen-inducible endothelial cell-specific Notch1 gene knockout mouse on atherosclerosis-prone ApoE-deficient background, was established. Mice were fed with high-fat-diet (HFD) along with or without Tamoxifen treatment (i.p. 2 mg/day for 5 consecutive days) starting from 4-wk old and terminated on 16-wk old. Aortas were harvested to study the effects of loss of Notch1 signaling in endothelial cells on the progression of aortic atherosclerosis. Deletion of Notch1 in endothelial cells was validated by immunostaining. Aortic plaque burden was evaluated by quantification of proportion of total aorta containing atherosclerosis detected by Oil-Red-O and hematoxylin-eosin staining using computer-aided image analysis. Blood was tested to measure lipid profile. Results: Notch1 is deleted from endothelial cells in Tamoxifen-treated mice. Loss of endothelial Notch1 signaling significantly decreased aortic plaque burden [n=10 (Tamoxifen -) and 12 (Tamoxifen +), P <0.05]. The serum levels of total cholesterol, HDL, LDL, triglycerides and glucose were comparable between Tamoxifen-treated and -untreated mice. Conclusions: Inactivation of endothelial Notch1 signaling inhibits atherosclerotic plaque formation. The decrease in atherosclerosis was not due to changes in the serum levels of total cholesterol, HDL, LDL, triglycerides and glucose. Our findings demonstrate that loss of Notch1 signaling in endothelial cells suppresses progression of atherosclerosis. It highlights Notch1 signaling as an emerging therapeutic target for the treatment of atherosclerosis.