gms | German Medical Science

Background: To analyze the potential role of the endogenous inhibitor of nitric oxide (NO) synthesis asymmetrical dimethylarginine (ADMA) and its degrading enzyme dimethylarginine dimethylaminohydrolase (DDAH) on in-vivo angiogenesis.

Methods: To determine if the effects of ADMA on angiogenesis could be reversed by overexpression of DDAH, we used DDAH 1 transgenic (TG) mice and wildytpe (WT) littermates (each n=42) and employed the disk angiogenesis system (DAS) as well as a murine model of hindlimb ischemia. Post surgery animals were treated with either PBS, or the NOS inhibitors ADMA or -nitro-L-arginine methyl ester (L-NAME; each 250µmol/kg/day) using osmoticwN minipumps. L-NAME is an exogenous NOS inhibitor that is not degraded by DDAH.

Results: Neovascularization in the DAS was significantly impaired by both NOS inhibitors. However, TG mice were resistant to the effects of ADMA and manifested greater neovascularization. Similarly, the angiogenic response (capillary density) to hindlimb ischemia was enhanced in TG mice. In addition, TG mice were resistant to the effects of ADMA on angiogenesis and had improved limb perfusion as measured by fluorescent microsphere technique and indicated by microangiograms. Enhanced neovascularization and limb perfusion in the TG mice were associated with reduced plasma and tissue ADMA levels and enhanced tissue NOS enzyme activity.

Conclusion: Overexpression of the enzyme DDAH reduces levels of the endogenous NOS inhibitor ADMA, thereby increasing NO synthesis, and enhancing angiogenesis and limb perfusion. Therapeutic manipulation of DDAH expression or activity may represent a novel approach to restoring tissue perfusion.