Hypertension and endothelial dysfunction in apolipoprotein E knockout mice

Mice lacking ApoE (Apoe(-/-)) develop initially hypercholesterolemia and la tterly atherosclerosis, This study examined hemodynamics and endothelial fu nction in 6-week-old Apoe(-/-) mice with hypercholesterolemia only, 7.5-mon ths-old Apoe(-/-) mice with both hypercholesterolemia and atherosclerosis, and age matched controls. One day after implantation of catheters into the carotid artery, arterial pressure was measured in conscious, unrestrained m ice. Compared with the respective controls, there was a significant increas e in arterial pressure and the ratio of left ventricular weight to body wei ght in 7.5-month-old Apoe(-/-) mice but not in 6-week-old Apoe(-/-) mice. H istopathological analysis demonstrated significant renal artery disease in the form of extensive atheromatous plaques only in 7.5-month-old Apoe(-/-) mice, whereas no atherosclerotic lesions were found in 6-week-old Apoe(-/-) mice. For evaluation of endothelial function, a laser Doppler perfusion im ager with a computer-controlled optical scanner was used to measure cutaneo us blood perfusion on the dorsal side of one hind paw before and after topi cal application of mustard oil, which is known to induce nitric oxide-media ted vasodilation. The mustard oil treatment elicited a substantial increase in blood perfusion (P<0.01), which was similar between 6-week-old Apoe(-/- ) mice and controls but significantly blunted in 7.5-month-old Apoe(-/-) mi ce versus control mice, suggesting nitric oxide-mediated vasodilation is di minished in 7.5-month-old Apoe(-/-) mice but not in 6-week-old Apoe(-/-) mi ce. In contrast, the increase in blood perfusion induced by topical adminis tration of cilostazol, which induces vasodilation via cyclic adenosine mono phosphate, was not different between 7.5-month-old Apoe(-/-) mice and contr ols. Thus hypertension and endothelial dysfunction observed in 7.5-month-ol d Apoe(-/-) mice may be due mainly to atherosclerosis.