TAMOXIFEN DECREASES THE RATE OF PROLIFERATION OF RAT VASCULAR SMOOTH-MUSCLE CELLS IN CULTURE BY INDUCING PRODUCTION OF TRANSFORMING GROWTH-FACTOR-BETA

Tamoxifen selectively and reversibly decreased the rate of proliferation of adult rat aortic vascular smooth-muscle cells (VSMCs). Half-maximal inhibition of proliferation occurred at 2-5 muM tamoxifen for VSMCs and at > 50 muM for adventitial fibroblasts. The cell cycle time for all the VSMCs in the population was increased from 35+/-2 h to 54+/- 4 h in the presence of 33 muM tamoxifen. Tamoxifen did not affect the time of entry into DNA synthesis, but delayed arrival at mitosis by >24 h. It therefore extended the duration of the G2-to-M phase of the cell cycle. However, the rate of proliferation of VSMCs was not decreased by tamoxifen (at concentrations up to 50 muM) in the presence of neutralizing antibody to transforming growth factor beta (TGF-beta). The level of mRNA for TGF-beta1 in VSMCs was strongly induced by 10 muM tamoxifen, and TGF-beta activity in conditioned medium from tamoxifen-treated cells was more than 50-fold higher than from control cells. Tamoxifen therefore extended the G2-to-M phase of the cell cycle in VSMCs by increasing TGF-beta activity in the culture.