['Many angiogenic factors require endothelium-derived nitric oxide (NO) to exert their effects. Recently, an endogenous competitive antagonist of NO synthase has been characterized: asymmetric dimethylarginine (ADMA). Elevated plasma levels of ADMA reduce NO synthesis in hypercholesterolemia. Accordingly, we hypothesized that hypercholesterolemia impairs angiogenesis by an ADMA-dependent mechanism.', 'Angiogenesis was assessed with the use of a disk angiogenesis system implanted subcutaneously in normal (E(+)) mice or apolipoprotein (apo)E-deficient hypercholesterolemic (E(-)) mice. After 2 weeks, the disks were removed, and the fibrovascular growth area was used as an index of angiogenesis. Basal and fibroblast growth factor-stimulated angiogenesis was impaired in E(-) mice, associated with an elevation in plasma ADMA. Oral administration of L-arginine reversed the impairment of angiogenesis in E(-) mice. By contrast, oral administration of L-nitroarginine (an exogenous antagonist of NO synthase) reduced angiogenesis. When added directly to the disk, ADMA dose-dependently inhibited basal and fibroblast growth factor-induced angiogenesis, an effect that was reversed by oral administration of L-arginine.'] Is angiogenesis impaired by hypercholesterolemia : role of asymmetric dimethylarginine?