TGF-beta promotes proliferation of cultured SMC via both PDGF-AA-dependent and PDGF-AA-independent mechanisms.

Transforming growth factor-,61 (TGF-,81) has been implicated in mediating smooth muscle cell (SMC) growth after vascular injury. Studies examining TGF-fi-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 TGF-#t also may have delayed growth effects independent of PDGF-AA. The aims of the present studies were to examine the effects of TGF-#t on chronic growth re- sponses of cultured SMC. Results demonstrated that TGF-ft elicited a delayed growth response (24 fold increase in 3H-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 TGF-ft-induced growth. Co-treatment with TGF-ft 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. Neutral- izing 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-ft induces marked delayed growth responses, alone and in combi- nation with EGF, bFGF or PDGF-BB, that are largely independent of PDGF-AA. (J. Clin. Invest.