Effects of endogenous nitric oxide and of DETA NONOate in arteriogenesis.
Previous studies showed that targeted endothelial nitric oxide synthase (eNOS) disruption in mice with femoral artery occlusion does not impede and transgenic eNOS overexpression does not stimulate collateral artery growth after femoral artery occlusion, suggesting that nitric oxide from eNOS does not play a role in arteriogenesis. However, pharmacologic nitric oxide synthase inhibition with L-NAME markedly blocks arteriogenesis, suggestive of an important role of nitric oxide. To solve the paradox, we studied targeted deletion of eNOS and of inducible nitric oxide synthase (iNOS) in mice and found that only iNOS knockout could partially inhibit arteriogenesis. However, the combination of eNOS knockout and treatment with the iNOS inhibitor L-NIL completely abolished arteriogenesis. mRNA transcription studies (reverse transcriptase-polymerase chain reaction) performed on collateral arteries of rats showed that eNOS and especially iNOS (but not neural nitric oxide synthase) become upregulated in shear stress-stimulated collateral vessels, which supports the hypothesis that nitric oxide is necessary for arteriogenesis but that iNOS plays an important part. This was strengthened by the observation that the nitric oxide donor DETA NONOate strongly stimulated collateral artery growth, activated perivascular monocytes, and increased proliferation markers. Shear stress-induced nitric oxide may activate the innate immune system and activate iNOS. In conclusion, arteriogenesis is completely dependent on the presence of nitric oxide, a large part of it coming from mononuclear cells.
Troidl
Kerstin
K
Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
Tribulova
Silvia
S
Cai
Wei-Jun
WJ
Rüding
Inka
I
Apfelbeck
Hanna
H
Schierling
Wilma
W
Troidl
Christian
C
Schmitz-Rixen
Thomas
T
Schaper
Wolfgang
W
D000818:Animals; D001158:Arteries / Q000187:drug effects* / Q000254:growth & development*; D003097:Collateral Circulation / Q000187:drug effects / Q000502:physiology; D055786:Gene Knockout Techniques; D018390:Gene Targeting; D051379:Mice; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology; D009603:Nitroso Compounds / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley
D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; C094210:2,2'-(hydroxynitrosohydrazono)bis-ethanamine; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D019331:NG-Nitroarginine Methyl Ester