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Role of PDGF-A expression in the control of vascular smooth muscle cell growth by transforming growth factor-beta
R A Majack1, M W Majesky, L V Goodman
1Upjohn Company, Kalamazoo, Michigan 49001.
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 its induction by PDGF and, based on cycloheximide experiments, appeared to depend on the de 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 determined 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.
Insights
Transforming growth factor-beta (TGF-beta) promotes vascular smooth muscle cell (SMC) proliferation by upregulating PDGF-A expression. This study identifies PDGF-A as a key mediator of TGF-beta
Area of Science:
- Cell Biology
- Molecular Biology
- Vascular Biology
Background:
- Transforming growth factor-beta (TGF-beta) exhibits dual roles in regulating vascular smooth muscle cell (SMC) proliferation, influenced by cell density.
- Understanding the mechanisms behind TGF-beta's growth-promoting effects in confluent SMCs is crucial for vascular research.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying the growth-promoting effects of TGF-beta in confluent SMC cultures.
- To investigate the role of specific growth factors and their mediators in TGF-beta-induced SMC proliferation.
Main Methods:
- Mitogenesis assays were performed using confluent SMCs treated with TGF-beta, serum, PDGF, and bFGF.
- Gene and protein expression of PDGF-A and thrombospondin were analyzed following TGF-beta treatment.
- Cycloheximide experiments were used to assess the dependence on de novo protein synthesis.
- The mitogenic effects of purified PDGF-AA homodimers were evaluated in combination with other growth factors.
Main Results:
- TGF-beta potentiated the mitogenic effects of serum, PDGF, and bFGF on confluent SMCs and acted as an individual mitogen.
- TGF-beta regulated the expression of PDGF-A and thrombospondin, key mediators of SMC proliferation.
- Thrombospondin induction was density-dependent and delayed, suggesting dependence on intermediary protein synthesis (likely PDGF-A).
- PDGF-A was identified as the biological mediator of TGF-beta's growth-stimulatory effects on confluent SMCs.
- PDGF-AA homodimers demonstrated mitogenic activity for SMCs, especially when combined with bFGF and PDGF-BB.
Conclusions:
- TGF-beta promotes the growth of confluent SMCs through mechanisms involving the upregulation of PDGF-A.
- PDGF-A acts as a critical mediator in TGF-beta-induced SMC proliferation.
- The findings provide insights into the complex interplay of growth factors in vascular cell growth regulation.