Effects of transforming growth factor-betas on endothelial anticoagulant activity

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To investigate the effects of transforming growth factor-betas (TGF-betas) on endothelial anticoagulant activity, we assayd thrombomodulin (TM) activity and antigen levels of human umbilical vein endothelial cells (HUVECs) incubated with TGF-betas in vitro. TGF-beta1 suppressed surface TM activity and surface TM antigen levels maximally 12 h after incubation by dose-dependent manners. TGF-beta2 was almost equipotent with TGF-beta1 for the suppression of them. Both TGF-betas suppressed total TM antigen level in HUVECs, and the time course of the suppression was similar to that of the cell surface TM antigen level. The maximal reductions of TM mRNA levels by TGF-betas were observed at several hours ahead of those observed in both surface and total TM antigen levels, suggesting that the TGF-beta-mediated suppression of TM antigen of HUVECs is primarily regulated at the TM mRNA level. Our present work suggests that the down-modulation of TM level induced by TGF-betas in HUVECs contributes in vivo to promoting the thrombogenesis either at the sites of injury of vessel walls, such as atherosclerotic lesions where TGF-beta1 is released from platelets, smooth muscle cells and monocytes, or at neovascular walls in tumors secreting TGF-beta2.