Overexpression of dimethylarginine dimethylaminohydrolase reduces tissue asymmetric dimethylarginine levels and enhances angiogenesis.
BACKGROUND
This study was designed to determine whether overexpression of the enzyme dimethylarginine dimethylaminohydrolase (DDAH) could enhance angiogenesis by reducing levels of the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA).


RESULTS
In DDAH1 transgenic (TG) and wild-type mice (each n=42), the role of DDAH overexpression on angiogenesis was studied by use of the disk angiogenesis system and a murine model of hindlimb ischemia (each n=21). After surgery, animals were treated with either PBS or the NOS inhibitors ADMA or N(omega)-nitro-L-arginine methyl ester (L-NAME; each 250 micromol x kg(-1) x d(-1)) by use of osmotic minipumps (each n=7). L-NAME was chosen to study an inhibitor that is not degraded by DDAH. Neovascularization in the disk angiogenesis system was impaired by both NOS inhibitors; however, TG animals were resistant to the effects of ADMA on neovascularization. Similarly, TG mice were more resistant to the inhibitory effect of ADMA on angioadaptation (angiogenesis and arteriogenesis) after hindlimb ischemia, as assessed by fluorescent microsphere studies and postmortem microangiograms. Enhanced neovascularization and limb perfusion in TG mice were associated with reduced plasma and tissue ADMA levels and enhanced tissue NOS enzyme activity.


CONCLUSIONS
We describe a novel mechanism by which DDAH regulates postnatal neovascularization. Therapeutic manipulation of DDAH expression or activity may represent a novel approach to restore tissue perfusion.
Jacobi
Johannes
J
Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, Calif 94305, USA.
Sydow
Karsten
K
von Degenfeld
Georges
G
Zhang
Ying
Y
Dayoub
Hayan
H
Wang
Bingyin
B
Patterson
Andrew J
AJ
Kimoto
Masumi
M
Blau
Helen M
HM
Cooke
John P
JP
D000581:Amidohydrolases / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D004790:Enzyme Induction; D005260:Female; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D007511:Ischemia / Q000503:physiopathology; D017078:Laser-Doppler Flowmetry; D051379:Mice; D008822:Mice, Transgenic; D008863:Microspheres; D018482:Muscle, Skeletal / Q000098:blood supply; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D018919:Neovascularization, Physiologic / Q000502:physiology*; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009573:Nitrites / Q000097:blood; D019736:Prostheses and Implants; D011993:Recombinant Fusion Proteins / Q000502:physiology
D009566:Nitrates; D009573:Nitrites; D011993:Recombinant Fusion Proteins; D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D001120:Arginine; D019001:Nitric Oxide Synthase; D000581:Amidohydrolases; C059999:dimethylargininase; D019331:NG-Nitroarginine Methyl Ester