EDN1 and Alzheimer disease: Sustained hypoperfusion and oxidative stress, both primary features of aged brain tissue during the prodromal stages of AD [6, 12, 13], also may stimulate the expression of various NOS species and subsequent ET-1 in brain cells and probably increase the accumulation of oxidative stress products, thereby contributing to blood-brain barrier (BBB) breakdown, increased NO, and peroxynitrite production and resulting in brain parenchymal cell damage (for a more in-depth discussion regarding the interactions of each of these factors please see our previous works [10, 14]).