EDN1 and migraine disorder: However, with respect to migraine aura, this traditional controversy between the vascular and neuronal theory dissolved when it became clear that epipial, i.e., abluminal, application of the vasoconstrictor polypeptide endothelin-1 is currently the most potent trigger of spreading depolarization in rodents in vivo and that endothelin-1 has this effect because of its vasoconstrictor properties, causing an imbalance between energy supply and demand of neurons (Dreier et al., 2002a).