TGF-BETA PROMOTES PROLIFERATION OF CULTURED SMC VIA BOTH PDGF-AA-DEPENDENT AND PDGF-AA-INDEPENDENT MECHANISMS

Transforming growth factor-beta 1 (TGF-beta 1) has been implicated in mediating smooth muscle cell (SMC) growth after vascular injury. Studies examining TGF-beta-induced growth of cultured SMC have identified only modest mitogenic effects which are largely dependent on autocrine production of platelet-derived growth factor-AA (PDGF-AA). Recent studies have suggested, however, that TGP-beta also may have delayed growth effects independent of PDGF-AA. The aims of the present studies were to examine the effects of TGF-beta on chronic growth responses of cultured SMC. Results demonstrated that TGF-beta elicited a delayed growth response (24 fold increase in H-3-TdR incorp. from 48-72 h) and enhanced SMC production of PDGF-AA (eightfold increase at 24 h). Neutralizing antibodies to PDGF-AA, however, inhibited only 10-40% of delayed TGP-beta-induced growth. Co-treatment with TGF-beta transiently delayed epidermal growth factor (EGF)-, basic fibroblast growth factor (bFGF)-, or PDGF-BB-induced entry into S phase but enhanced the delayed growth responses to these growth factors by 16.0-, 5.8-, or 4.2-fold, respectively. Neutralizing antibodies to PDGF-AA had no effect on these synergistic responses and exogenous PDGF-AA did not increase growth responses to EGF, bFGF, or PDGF-BB. In summary, TGF-beta induces marked delayed growth responses, alone and in combination with EGF, bFGF or PDGF-BB, that are largely independent of PDGF-AA.