gms | German Medical Science

28. Wissenschaftlicher Kongress der Deutschen Hochdruckliga

24. bis 27.11.2004, Hannover

ADMA impairs angiogenesis and limb perfusion in a murine model of hindlimb ischemia

Asymmetrisches Dimethylarginin (ADMA) hemmt die Angiogenese und Arteriogenese im Hinterlaufischämiemodell der Maus

Meeting Abstract (Hypertonie 2004)

  • J. Jacobi - Universität Erlangen-Nürnberg, Dept. of Cardiovascular Medicine
  • K. Sydow - Universität Erlangen-Nürnberg, Dept. Cardiovascular Medicine
  • G. von Degenfeld
  • Y. Zhang - Baxter Laboratory of Genetic Pharmacology
  • B. Wang - Dept. of Anaesthesiology
  • A. Patterson
  • M. Kimoto - Okayama Prefectural University
  • H. Blau
  • J. Cooke

Hypertonie 2004. 28. Wissenschaftlicher Kongress der Deutschen Hochdruckliga. Hannover, 24.-27.11.2004. Düsseldorf, Köln: German Medical Science; 2005. Doc04hochP2

The electronic version of this article is the complete one and can be found online at:

Published: August 10, 2005

© 2005 Jacobi et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( You are free: to Share – to copy, distribute and transmit the work, provided the original author and source are credited.



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.