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 proliferati on of adult rat aortic vascular smooth-muscle cells (VSMCs). Half-maxi mal inhibition of proliferation occurred at 2-5 muM tamoxifen for VSMC s 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 >2 4 h. It therefore extended the duration of the G2-to-M phase of the ce ll cycle. However, the rate of proliferation of VSMCs was not decrease d by tamoxifen (at concentrations up to 50 muM) in the presence of neu tralizing antibody to transforming growth factor beta (TGF-beta). The level of mRNA for TGF-beta1 in VSMCs was strongly induced by 10 muM ta moxifen, and TGF-beta activity in conditioned medium from tamoxifen-tr eated cells was more than 50-fold higher than from control cells. Tamo xifen therefore extended the G2-to-M phase of the cell cycle in VSMCs by increasing TGF-beta activity in the culture.