Angiogenesis is impaired by hypercholesterolemia: role of asymmetric dimethylarginine.
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.


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.
Jang
J J
JJ
Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305-5406, USA.
Ho
H K
HK
Kwan
H H
HH
Fajardo
L F
LF
Cooke
J P
JP
D020533:Angiogenesis Inhibitors / Q000037:antagonists & inhibitors / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D001057:Apolipoproteins E / Q000097:blood* / Q000172:deficiency; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006937:Hypercholesterolemia / Q000097:blood / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000097:blood
D020533:Angiogenesis Inhibitors; D001057:Apolipoproteins E; D004791:Enzyme Inhibitors; D016222:Fibroblast Growth Factor 2; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase