NITRIC-OXIDE INHIBITION OF ENDOTHELIAL-CELL MITOGENESIS AND PROLIFERATION

Background. Endothelial cell (EC) proliferation is essential in vascul ar repair after injury to the vessel wall. Impaired EC proliferation m ay be an important factor contributing to vessel wall disease. Nitric ic oxide (NO) inhibits proliferation of manqy cells, including smooth mucscle cells (SMC). We tested the hypothesis that NO inhibits EC prol iferation and DAIA synthesis. Methods, Cultured canine venous ECs were treated with NO donors: S-n itroso-N-acet)lpenicillamine (SNAP), S-ni troso-glutathione (GSNO) or spermine NONOate (SP NO). Proliferation te as determined by cell counts after 48 hours. Parallel proliferation st udies were done with rat aortic SMC. ECs synchronized in S phase were treated with the NO donor diethylamine NONOate (DEA NO), and DNA synth esis; was measured as the incorporation of tritiated thymidine. A NO a ntagonist, cPTIO, was used to reverse the effects of DEA NO. Results. Concentration-dependent (1 to 100 mmol/L) ingibition of EC proliferati on (11% to 71% inhibition; p < 0.05) was seen with SNAP. Similar inhib ition of proliferation was noted with the NO donors GSNO and SPNO and in SMC treated with SNAP. DEA NO caused concentration-dependent (0.1 t o 1 mmol/L) inhibition of EC DNA synthesis (39% to 85% inhibition; p < 0.05), which was reversed by cPTIO. Conclusions. NO inhibits prolifer ation and mitogenesis of cultured ECs. This may occur in certain patho logic states, where production of NO in plaques and diseased vessels i mpedes reendothelialization, thus contributing to adverse thrombotic a nd vasospastic events.