Role of PDGF-A expression in the control of vascular smooth muscle cell growth by transforming growth factor-beta.

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Abstract
Transforming growth factor-.beta. (TGF-.beta.) is a multifunctional regulatory peptide that can inhibit or promote the proliferation of cultured vascular smooth muscle cells (SMCs), depending on cell density (Majack, R. A. 1987. J. Cell Biol, 105: 465-471). In this study, we have examined the mechanisms underlying the growth-promoting effects of TGF-.beta. in confluent SMC cultures. In mitogenesis assays using confluent cells, TGF-.beta. was found to potentiate the stimulatory effects of serum, PDGF, and basic fibroblast growth factor (bFGF), and was shown to act individually as a mitogen for SMC. In gene and protein expression experiments, TGF-.beta. was found to regulate the expression of PDGF-A and thrombospondin, two potential mediators of SMC proliferative events. The induction of thrombospondin protein and mRNa was density-dependent, delayed relative to this induction by PDGF and, based on cycloheximide experiments, appeared to depend on the do novo synthesis of an intermediary protein (probably PDGF-A). The relationship between PDGF-A expression and TGF-.beta.-mediated mitogenesis was investigated, and it was determine that a PDGF-like activity (probably PDGF-A) was the biological mediator of the growth-stimulatory effects of TGF-.beta. on confluent SMC. The effects of purified homodimers of PDGF-A on SMC replication were investigated, and it was determined that PDGF-AA was mitogenic for cultured SMC, particularly when used in combination with other growth factors such as bFGF and PDGF-BB. The data suggest several molecular mechanisms that may account for the ability of TGF-.beta. to promote the growth of confluent SMC in culture.

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