TRANSFORMING GROWTH FACTOR-BETA-1 IS A POWERFUL MODULATOR OF PLATELET-DERIVED GROWTH-FACTOR ACTION IN VASCULAR SMOOTH-MUSCLE CELLS

We have studied the effect of transforming growth factor beta-1 (TGF-beta-1) on vascular smooth muscle cell (SMC) mitogenesis and expression of thrombospondin and other growth related genes. We found that TGF-beta-1 treatment of vascular SMC induced a prolonged increase in steady-state mRNA levels of thrombospondin as well as alpha-1(IV) collagen. The increase began at approximately 2 h, peaked by 24 h, and remained considerably elevated 48 h after growth factor addition. There was a corresponding increase in thrombospondin protein as well as increased expression of several other secreted polypeptides. The increase in thrombospondin contrasted sharply with that observed for platelet-derived growth factor (PDGF) which induced a rapid and transient increase in thrombospondin mRNA level. Although TGF-beta-1 was able to directly enhance expression of thrombospondin as well as the growth-related genes c-fos and c-myc, and induced c-fos expression with identical kinetics as PDGF, it was unable to elicit [H-3]thymidine incorporation into DNA in three independent smooth muscle cell strains. However, TGF-beta-1 was able to strongly increase the mitogenic response of SMC to PDGF. Addition of both TGF-beta-1 and PDGF to SMC also caused a synergistic increase in the expression of thrombospondin as well as c-myc. Interestingly, in one other smooth muscle cell strain, a weak and delayed mitogenic response to TGF-beta-1 alone was observed. Our results strongly suggest that induction of thrombospondin expression by TGF-beta-1 and by PDGF occurs by distinct mechanisms. In addition, that TGF-beta-1 can enhance PDGF-induced mitogenesis may be due to the ability of TGF-beta-1 to directly induce the expression of thrombospondin, c-fos, c-myc, and the PDGF beta-receptor.