This Article Order Full text via Infotrieve Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Leszczynski, D. Articles by Foegh, M. L. Search for Related Content PubMed PubMed Citation Articles by Leszczynski, D. Articles by Foegh, M. L.

American Journal of Pathology, Vol 142, 149-155, Copyright © 1993 by American Society for Investigative Pathology

REGULAR ARTICLES

Direct and endothelial cell-mediated effect of cyclosporin A on the proliferation of rat smooth muscle cells in vitro

D Leszczynski, Y Zhao, TJ Yeagley and ML Foegh
Department of Surgery, Georgetown University Medical Center, Washington, DC.

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.

This article has been cited by other articles:

				R. G. Masters, R. A. Davies, J. P. Veinot, P. J. Hendry, S. J. Smith, and A. J. de Bold Discoordinate Modulation of Natriuretic Peptides During Acute Cardiac Allograft Rejection in Humans Circulation, July 20, 1999; 100(3): 287 - 291. [Abstract] [Full Text] [PDF]

				H. O. Andersen, B. F. Hansen, P. Holm, S. Stender, and B. G. Nordestgaard Effect of Cyclosporine on Arterial Balloon Injury Lesions in Cholesterol-Clamped Rabbits : T Lymphocyte–Mediated Immune Responses Not Involved in Balloon Injury–Induced Neointimal Proliferation Arterioscler. Thromb. Vasc. Biol., July 1, 1999; 19(7): 1687 - 1694. [Abstract] [Full Text] [PDF]

				K. B. Lemstrom, A. K. Raisanen-Sokolowski, P. J. Hayry, and P. K. Koskinen Triple Drug Immunosuppression Significantly Reduces Aortic Allograft Arteriosclerosis in the Rat Arterioscler. Thromb. Vasc. Biol., April 1, 1996; 16(4): 553 - 564. [Abstract] [Full Text]