This study investigated endothelial dysfunction in Alzheimer's disease by testing bosentan, an antagonist of the vasoconstricting peptide endothelin-1 (ET-1), on Tg2576 mice. Past studies have demonstrated Aβ may induce endothelial dysfunction of cerebral and systemic vessels, and several findings suggest that vascular factors may play a major role in Alzheimer's disease. Results in this study show endothelium-dependent aortic vasorelaxation being attenuated in Tg2576 mice, compared to both wildtype and Tg2576 mice treated with bosentan. There was no difference between the three groups in response to nitroprusside. This study demonstrates endothelial dysfunction in the arteries of mice overexpressing APP and suggests a pathophysiological role for the endothelial system in AD.