TRANSFORMING GROWTH-FACTOR BETA1 AND BETA2 INDUCE DOWN-MODULATION OF THROMBOMODULIN IN HUMAN UMBILICAL VEIN ENDOTHELIAL-CELLS

To investigate the effects of transforming growth factor-betas (TGF-be ta s) on endothelial anticoagulant activity, we assayed thrombomodulin (TM) activity and antigen levels of human umbilical vein endothelial cells (HUVECs) incubated with TGF-beta s in vitro. TGF-beta 1 suppress ed surface TM activity and surface TM antigen levels maximally 12 h af ter incubation in dose-dependent manners. TCF-beta 2 was almost equipo tent with TGF-beta 1 for the suppression of them. Both. TGF-beta s sup pressed total TM antigen level in HUVECs, acid the time course of the suppression was similar to that of the cell surface TMI antigen level. The maximal reductions of TM mRNA levels by TGF-beta s 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 T M antigen of HUVECs is primarily regulated at the TM mRNA level. Our p resent work suggests that the down-modulation of TM level induced by T GF-beta s in HUVECs contributes in vivo to promoting the thrombogenesi s either at the sites of injury of vessel walls, such as atherosclerot ic lesions where TGF-beta 1 is released from platelets, smooth muscle cells and monocytes, or at neovascular walls in tumors secreting TGF-b eta 2.