Abstract 224: Notch1 Activation in Endothelial Cells Promotes Progression of Atherosclerosis

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Introduction: Notch signaling plays pivotal roles in vascular development and cardiovascular disease. We previous showed that the Notch pathway is activated in luminal endothelial cells (EC) at atherosclerotic plaques, implicating a potential involvement of Notch signaling in atherosclerosis. We further demonstrated that loss of Notch1 signaling in EC suppresses progression of atherosclerosis. Here, we test the effect of activation of the Notch1 pathway in EC on atherosclerosis using mouse model with inducible EC-specific Notch1 activation on an ApoE -/- background. Methods: We created a Tamoxifen-inducible EC-specific N1IC (Notch1 intracellular domain, an active Notch1 mutant) expression mouse line on atherosclerosis-prone ApoE -/- background: ROSA LSL-N1IC /VE-cadherin-CreER T2 /ApoE -/- . 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 Notch1 activation in EC on the progression of aortic atherosclerosis. Expression of N1IC in EC 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: Enforced Notch1 activation in EC is induced in Tamoxifen-treated mice. EC gain-of-function Notch1 signaling significantly increased aortic plaque burden [n=10 in both (Tamoxifen -) and (Tamoxifen +) group, P <0.05]. The serum levels of total cholesterol, HDL, LDL, triglycerides and glucose were comparable between Tamoxifen-treated and -untreated mice. Conclusions: Activation of the Notch1 signaling pathway in EC facilitates atherosclerotic plaque formation. The increase in atherosclerosis was not due to changes in the serum levels of lipid, glucose, triglycerides, HDL, LDL and total cholesterol. Our findings demonstrate that activation of the Notch1 signaling pathway in EC promotes progression of atherosclerosis. It highlights Notch1 signaling as an emerging therapeutic target for the treatment of atherosclerosis.