aging and hypertension can 181223-80-3 impair endothelial function and inhibit the NO signalling pathway. In addition, impaired acetylcholine-induced endothelium-mediated aortic vasodilatation and reduction of NO bioavailability have been demonstrated during hypercholesterolemia in both animal and human studies, suggesting an important role of NO in dyslipidemia-induced vascular dysfunction. Apolipoprotein E-deficient mice are one of the most widely used animal model of atherosclerosis and abdominal aortic aneurysm . These mice develop hypercholesterolemia and aortic plaques when fed 
normal diet and Angiotensin II-Induced Endothelium Dysfunction accelerated atherosclerosis when fed a high fat western-type diet. It is now widely accepted that endothelial dysfunction is one of the early steps in atherosclerosis and AAA and altered NO signalling is a common feature observed in these animal models. Indeed, impairment of endothelium-mediated vasorelaxation in response to acetylcholine has been demonstrated in the aorta of ApoE2/2 mice fed a western-type diet. It is interesting to note that when fed a normal diet endotheliumdependent relaxation remains normal up to 6 months of age in ApoE2/2 mice. At older ages endothelial dysfunction is correlated with the development and size of aortic plaques. These findings suggest that the endothelial dysfunction is not simply mediated by hypercholesterolemia alone but likely involves additional mechanisms. Angiotensin II infusion is commonly used to promote atherosclerosis and AAA in ApoE2/2 mice. We have recently demonstrated that fenofibrate suppressed aortic dilatation and atherosclerosis via increasing eNOS activity in the AngII-infused mouse model, suggesting an important role of eNOS activity in this model. Although an increase in blood pressure has been reported in AngII-infused ApoE2/2 mice, impairment of endothelium-mediated relaxation and the underlying mechanism involved has not been fully explored in this mouse model. eNOS activity is tightly controlled by various membrane bound receptors and regulatory proteins under physiological conditions. Alternation of these receptors or regulatory proteins can upset the balanced generation of NO. Caveolae are 50100 nm cell surface plasma membrane invaginations which are abundant in endothelial cells. It has been suggested caveolae play an essential role in regulating NO production by interaction of eNOS and caveolin-1, a structural protein of caveolae. Pharmacological disruption of caveolae has been shown to impair NO- and endothelium-derived hyperpolarizing factor mediated acetylcholine-induced 9305921 vasodilatation in isolated rat blood vessels. Cav-1 has been associated with vascular diseases in both human and animal studies. In Cav-12/2 ApoE2/2 mice, atherosclerotic plaque area is markedly reduced despite the presence of hypercholesterolemia. Expression of Cav-1 mRNA and protein were reported to be significantly upregulated in diabetic mice and endothelium-dependent relaxation was markedly suppressed. In addition, it has been suggested recently that amlodipine, an L-type calcium channel blocker, can offer additional cardiovascular protective effects via enhancement of NO production in endothelial cells by antagonising the eNOS/Cav-1 signalling complex. These studies have provided evidence that eNOS/Cav-1 interactions could 10422886 be a novel target site for therapy of cardiovascular diseases. We hypothesized that AngII-infusion impaired vascular endothelium function was as