Angiogenesis is impaired by hypercholesterolemia - Role of asymmetric dimethylarginine

Article

关键词: NITRIC-OXIDE SYNTHASE;    FIBROBLAST GROWTH-FACTOR;    ENDOTHELIUM-DEPENDENT DILATION;    L-ARGININE;    IN-VITRO;    ENDOGENOUS INHIBITOR;    DEFICIENT MICE;    NO PRODUCTION;    RABBIT;    CELLS;   

DOI  :  10.1161/01.CIR.102.12.1414

来源: SCIE

【 摘 要 】

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 tan 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.

【 授权许可】

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