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 [3H]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.
Janat
M F
MF
Laboratory of Molecular Biology, American Red Cross, Jerome H. Holland Laboratory for Biomedical Sciences, Rockville, Maryland 20855.
Liau
G
G
D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics; D003513:Cycloheximide / Q000494:pharmacology; D004357:Drug Synergism; D015870:Gene Expression / Q000187:drug effects; D016762:Genes, fos; D016259:Genes, myc; D066298:In Vitro Techniques; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D010980:Platelet Membrane Glycoproteins / Q000235:genetics; D010982:Platelet-Derived Growth Factor / Q000008:administration & dosage*; D012333:RNA, Messenger / Q000235:genetics; D011817:Rabbits; D011956:Receptors, Cell Surface / Q000235:genetics; D017479:Receptors, Platelet-Derived Growth Factor; D019699:Thrombospondins; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000008:administration & dosage*
D010980:Platelet Membrane Glycoproteins; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D019699:Thrombospondins; D016212:Transforming Growth Factor beta; D003094:Collagen; D003513:Cycloheximide; D017479:Receptors, Platelet-Derived Growth Factor