Direct and endothelial cell-mediated effect of cyclosporin A on the proliferation of rat smooth muscle cells in vitro.
Cyclosporin A (CsA) has been suggested to potentiate graft vascular disease by stimulation of smooth muscle cell (SMC) proliferation. Both the in vitro and in vivo data are discordant, showing both stimulatory and inhibitory effects of CsA on vascular SMC proliferation. The direct and endothelial cell-mediated effects of CsA on vascular SMC proliferation were examined in vitro using the incorporation of [3H]thymidine. All experiments were done in serum-free conditions. The exposure of SMC to CsA (0.0001 to 0.1 micrograms/ml) had no effect on proliferation. High doses of CsA (0.5 to 10.0 micrograms/ml) were toxic to the SMC and endothelial cells; 90% of SMC population died within 3 to 6 days of exposure to 10.0 micrograms/ml CsA. In the studies on the endothelial cell-mediated effect of CsA, the endothelial cell-conditioned medium (ECCM) significantly increased SMC proliferation. This stimulatory effect was significantly attenuated when the ECCM was obtained from endothelial cells exposed to CsA. Endothelin (ET) is suggested to be an endothelial-cell-derived growth factor for SMC, and implicated as a possible cause of the uncontrolled proliferation of SMC during development of graft vascular disease. Exposure of SMC to levels of recombinant ET similar to the levels found in the ECCM (0.19 + 0.01 pg/ml) significantly increased SMC proliferation. CsA increased fivefold ET concentration in the ECCM. However, despite this rise in ET levels, there was a 45% decrease in SMC proliferation. In conclusion, CsA does not exert a direct modulatory effect on SMC proliferation in vitro, but may inhibit SMC proliferation indirectly via endothelial cell-derived factors. These unidentified factor(s) inhibit SMC proliferation and abolish the mitogenic effect of ET on SMC.
Leszczynski
D
D
Department of Surgery, Georgetown University Medical Center, Washington, DC.
Zhao
Y
Y
Yeagley
T J
TJ
Foegh
M L
ML
D000818:Animals; D002450:Cell Communication / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D017077:Culture Media, Conditioned; D016895:Culture Media, Serum-Free; D016572:Cyclosporine / Q000494:pharmacology*; D016232:Endothelins / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D009130:Muscle, Smooth / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D009206:Myocardium / Q000166:cytology; D051381:Rats
D017077:Culture Media, Conditioned; D016895:Culture Media, Serum-Free; D016232:Endothelins; D016572:Cyclosporine