The physiological function of amyloid precursor protein (APP) in the control of endothelial function during aging is unclear. Aortas of young (4-6 months old) and aged (23-26 months old) wild-type (WT) and endothelium-specific APP-deficient (eAPP−/−) mice were used to study aging-induced changes in vascular phenotype. Unexpectedly, aging significantly increased protein expression of APP in aortas of WT mice but not in aortas of eAPP−/− mice thereby demonstrating selective upregulation APP expression in vascular endothelium of aged aortas. Most notably, endothelial dysfunction (impairment of endothelium-dependent relaxations) induced by aging was significantly exacerbated in aged eAPP−/− mice aortas as compared to age-matched WT mice. Consistent with this observations, endothelial nitric oxide synthase (eNOS) protein expression was significantly decreased in aged eAPP−/− mice as compared to age matched WT mice. In addition, protein expression of cyclooxygenase 2 and release of prostaglandins were significantly increased in both aged WT and eAPP−/− mice. Notably, treatment with cyclooxygenase inhibitor, indomethacin, normalized endothelium-dependent relaxations in aged WT mice, but not in aged eAPP−/− mice. In aggregate, our findings support the concept that aging-induced upregulation of APP in vascular endothelium is an adaptive response designed to protect and preserve expression and function of eNOS.