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Stimulation of endothelial cells by doses of basic FGF-saporin that are lethal to smooth muscle cells
S Biro1, S Shrivastav1, Z X Yu1
1a Cardiology Branch, National Institutes of Health, Bethesda, Maryland, USA.
Abstract:
Basic fibroblast growth factor (FGF) receptors are up-regulated in proliferating (vs. quiescent) aortic smooth muscle cells, according to the results of recent studies. This up-regulation allows the ribosome inactivator saporin (if linked to basic FGF) to enter and kill proliferating, but not quiescent smooth muscle cells in vitro and in vivo. The authors now report that endothelial cells exhibit a different response. In 10% serum, FGF-SAP (0.1-1 nM) stimulates protein synthesis and cell division in subconfluent endothelial cells, but inhibits protein synthesis and cell division in subconfluent smooth muscle cells. Endothelial cells were inhibited at 10 nM FGF-SAP. A stimulatory response was seen in smooth muscle cells only at 0.1 nM FGF-SAP, and only after serum deprivation. Both cell types were resistant to FGF-SAP at high cell density. These responses correlated with FGF receptor density, which was sixfold higher in smooth muscle than endothelial cells and twice as high in serum-free smooth muscle cells as in serum-deprived smooth muscle cells. Moreover, a dose of FGFSAP that inhibited neointimal smooth muscle accumulation after balloon injury did not inhibit reendothelialization. Thus, there is a dose range at which FGF-SAP has unique properties that may make it useful in the treatment of vascular injury.
Insights
Basic fibroblast growth factor-saporin (FGF-SAP) uniquely targets vascular cells. It stimulates endothelial cells while inhibiting smooth muscle cells, offering potential for vascular injury treatment.
Area of Science:
- Vascular Biology
- Cell Signaling
- Drug Development
Background:
- Basic fibroblast growth factor (FGF) receptors are upregulated in proliferating smooth muscle cells.
- FGF-linked saporin (FGF-SAP) selectively targets and eliminates proliferating smooth muscle cells.
- Endothelial cells display distinct responses to FGF-SAP compared to smooth muscle cells.
Purpose of the Study:
- To investigate the differential effects of FGF-SAP on endothelial and smooth muscle cells.
- To explore the role of FGF receptor density in mediating these cellular responses.
- To assess the therapeutic potential of FGF-SAP in vascular injury models.
Main Methods:
- Treatment of subconfluent and confluent endothelial and smooth muscle cells with varying concentrations of FGF-SAP in different serum conditions.
- Measurement of protein synthesis and cell division.
- Quantification of FGF receptor density.
- Evaluation of FGF-SAP efficacy in a balloon injury model of vascular injury.
Main Results:
- FGF-SAP (0.1-1 nM) stimulated endothelial cells but inhibited smooth muscle cells in 10% serum.
- Higher FGF-SAP concentrations (10 nM) inhibited endothelial cells.
- Smooth muscle cell stimulation occurred only at 0.1 nM FGF-SAP after serum deprivation.
- Cell density and FGF receptor density influenced cellular responses.
- FGF-SAP inhibited neointimal smooth muscle accumulation without affecting reendothelialization post-balloon injury.
Conclusions:
- FGF-SAP exhibits dose-dependent and cell-type-specific effects on vascular cells.
- FGF receptor density is a key determinant of FGF-SAP response.
- A specific dose range of FGF-SAP demonstrates potential for treating vascular injury by selectively targeting smooth muscle cells without impairing reendothelialization.
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