Nitric oxide inhibition of endothelial cell mitogenesis and proliferation.
BACKGROUND
Endothelial cell (EC) proliferation is essential in vascular repair after injury to the vessel wall. Impaired EC proliferation may be an important factor contributing to vessel wall disease. Nitric oxide (NO) inhibits proliferation of many cells, including smooth muscle cells (SMC). We tested the hypothesis that NO inhibits EC proliferation and DNA synthesis.


METHODS
Cultured canine venous ECs were treated with NO donors: S-nitroso-N-acetylpenicillamine (SNAP), S-nitroso-glutathione (GSNO), or spermine NONOate (SP NO). Proliferation was determined by cell counts after 48 hours. Parallel proliferation studies were done with rat aortic SMC. ECs synchronized in S phase were treated with the NO donor diethylamine NONOate (DEA NO), and DNA synthesis was measured as the incorporation of tritiated thymidine. A NO antagonist, cPTIO, was used to reverse the effects of DEA NO:


RESULTS
Concentration-dependent (1 to 100 mmol/L) inhibition of EC proliferation (11% to 71% inhibition; p < 0.05) was seen with SNAP. Similar inhibition of proliferation was noted with the NO donors GSNO and SP NO and in SMC treated with SNAP. DEA NO caused concentration-dependent (0.1 to 1 mmol/L) inhibition of EC DNA synthesis (39% to 85% inhibition; p < 0.05), which was reversed by cPTIO.


CONCLUSIONS
NO inhibits proliferation and mitogenesis of cultured ECs. This may occur in certain pathologic states, where production of NO in plaques and diseased vessels impedes reendothelialization, thus contributing to adverse thrombotic and vasospastic events.
Sarkar
R
R
Department of Physiology and the Section of Vascular Surgery, Department of Surgery, University of Michigan Medical School, Ann Arbor, USA.
Webb
R C
RC
Stanley
J C
JC
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004285:Dogs; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D005978:Glutathione / Q000031:analogs & derivatives / Q000494:pharmacology; D006834:Hydrazines / Q000494:pharmacology; D008297:Male; D008934:Mitogens / Q000494:pharmacology*; D009569:Nitric Oxide / Q000502:physiology*; D009589:Nitrogen Oxides; D009603:Nitroso Compounds / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D016196:S Phase; D026423:S-Nitroso-N-Acetylpenicillamine; D026422:S-Nitrosoglutathione; D013096:Spermine / Q000031:analogs & derivatives / Q000494:pharmacology
D006834:Hydrazines; D008934:Mitogens; D009589:Nitrogen Oxides; D009603:Nitroso Compounds; C091861:spermine nitric oxide complex; D013096:Spermine; D009569:Nitric Oxide; D026422:S-Nitrosoglutathione; D026423:S-Nitroso-N-Acetylpenicillamine; C084012:1,1-diethyl-2-hydroxy-2-nitrosohydrazine; D004247:DNA; D005978:Glutathione; D010396:Penicillamine