Nitric oxide reversibly inhibits the migration of cultured vascular smooth muscle cells.
Augmentation of nitric oxide (NO) production in vivo decreases lesions in a variety of models of arterial injury, and inhibition of NO synthase exacerbates experimental intimal lesions. Both vascular smooth muscle cell (VSMC) proliferation and migration contribute to lesion formation. Although NO inhibits VSMC proliferation, its effects on VSMC migration are unknown. To test the hypothesis that NO inhibits VSMC migration independent of inhibition of proliferation, we examined migration of rat aortic VSMCs after wounding of a confluent culture in the presence of chemical donors of NO. Hydroxyurea was used to eliminate any confounding effect of NO on proliferation. Three NO donors, diethylamine NONOate, spermine NONOate, and S-nitrosoglutathione, exhibited concentration-dependent inhibition of both number of migrating VSMCs and maximal distance migrated. Inhibition of migration was also seen with 8-Br-cGMP, suggesting that activation of guanylate cyclase may play a role in mediating the antimigratory effects of NO. Migration resumed after removal of NO donors, as evidenced by an increase in distance migrated. Measurement of VSMC protein synthesis and mitochondrial respiration indicated that inhibition of migration by NO donors was not due to metabolic cytostasis. These findings indicate that NO reversibly inhibits VSMC migration independent of proliferation or cytotoxicity, a novel mechanism by which both endogenous and pharmacological NO may alter vascular pathology.
Sarkar
R
R
Department of Physiology, University of Michigan Medical School, Ann Arbor 48109-0622, USA. rsarkar@ucla.edu
Meinberg
E G
EG
Stanley
J C
JC
Gordon
D
D
Webb
R C
RC
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D005978:Glutathione / Q000031:analogs & derivatives* / Q000494:pharmacology; D006834:Hydrazines / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology*; D009589:Nitrogen Oxides; D009603:Nitroso Compounds / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D026422:S-Nitrosoglutathione
D006834:Hydrazines; D009589:Nitrogen Oxides; D009603:Nitroso Compounds; D009569:Nitric Oxide; D026422:S-Nitrosoglutathione; C084012:1,1-diethyl-2-hydroxy-2-nitrosohydrazine; D005978:Glutathione