olite level was significantly lower in AngII-infused mice . Effect of Methyl-b-cyclodextrin on Acetylcholine-induced Relaxation in Isolated 12149260 Aortas from Vehicle- and AngIIinfused ApoE2/2 Mice The effect of chemical disruption of caveolae on acetylcholineinduced relaxation was studied in isolated aortas of vehicle- and AngII-infused mice. The isolated aortas were preincubated either with methyl-b-cyclodextrin or without for 60 minutes prior to construction of concentration-response curves. Neither MbCD or non- MbCD pre-incubation influenced baseline tone at any time. In the presence of MbCD, the acetylcholineinduced relaxation in isolated aortas from AngII-infused mice was Angiotensin II-Induced Endothelium Dysfunction significantly greater at 3 mM with a leftward shift of the Angiotensin II-Induced Endothelium Dysfunction induced relaxation in isolated aortas from the vehicle-infused mice . Discussion This study demonstrates for the first time that an increase in caveolin-1 protein expression is associated with the impairment of acetylcholine-induced endothelium-dependent aortic relaxation found in AngII-infused ApoE2/2 mice. It is well known that malfunction of the endothelium is a hallmark of vascular diseases seen in patients with hypertension and atherosclerosis. Our results suggest that upregulation of caveolin-1 protein expression and reduced NO bioavailability contributes to aortic endothelial dysfunction in AngII-infused ApoE2/2 mice. Classically, relaxation of blood vessels by acetylcholine is mediated by NO generated from eNOS and activation of soluble guanylyl cyclase. Previous studies have demonstrated that acetylcholine, but not DEA-NONOate, induced vascular relaxation was reduced in hypercholesterolemic ApoE2/ 2 mice. Similarly, in this study, we observed a marked decrease in acetylcholine-induced aortic relaxation in AngIIinfused ApoE2/2 mice suggesting reduction of eNOS activity. It is important to note that the acetylcholine-induced relaxation was substantially inhibited by L-NAME, an eNOS inhibitor, confirming that the relaxation was 
mediated by eNOS-derived NO. Although altered responsiveness to NO in vascular smooth muscle cells has been observed in ApoE2/2 mice, the preserved SNP-induced endothelium-independent relaxation observed in our current study suggests the impaired relaxation was not a consequence of changes in soluble guanylyl cyclase activity and/or subsequent cGMP formation in VSMCs. An enhanced vasoconstriction response to purchase AIC316 a-adrenoceptor agonist without alteration in endothelium function was previously reported in ApoE2/2 mice. We observed that the increased vasoconstriction response was not limited to an a-adrenoceptor agonist, but was also demonstrated in response to KCl in AngIIinfused mice. The possible explanation for this alteration in both receptor-mediated and non-receptor-mediated vasoconstriction is that endothelial NO is basally released as a buffering mechanism limiting the magnitude of vascular contraction response under normal physiological conditions. In the case of 9346307 endothelial dysfunction, this balance could be upset resulting in an enhanced contraction response. In agreement with this hypothesis, we noticed a significant reduction in plasma nitrite and nitrate levels in AngII-infused mice. A reduced phenylephrine-induced aortic contraction was reported in hypercholesteremic rabbits in association with an alteration of the cyclooxygenase signalling pathway. In this study, plasma cholestero