Background—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.

Methods and Results—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.

Conclusions—The derangement of the NO synthase pathway that occurs in hypercholesterolemia is associated with an impairment of angiogenesis. The lipid-induced impairment of angiogenesis can be reversed by oral administration of l-arginine and can be mimicked in normocholesterolemic animals by administration of an NO synthase antagonist. The data are consistent with the hypothesis that ADMA is an endogenous inhibitor of angiogenesis.