(Circulation. 2000;102:1414.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Angiogenesis Is Impaired by Hypercholesterolemia
Role of Asymmetric Dimethylarginine
From the Division of Cardiovascular Medicine (J.J.J., H.-K.V.H., J.P.C.) and the Department of Pathology (H.H.K., L.F.F.), Stanford University School of Medicine, Stanford, Calif; and Pathology Service, Veterans Affairs Medical Center, Palo Alto, Calif.
Correspondence to John P. Cooke, MD, PhD, Division of Cardiovascular Medicine, Stanford University School of Medicine, 300 Pasteur Dr, Stanford, CA 94305-5406. E-mail John.Cooke{at}stanford.edu
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.
Key Words: angiogenesis • nitric oxide • hypercholesterolemia
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