Heparin-binding growth factor-1 stimulation of human endothelial cells induces platelet-derived growth factor A-chain gene expression.
Heparin-binding growth factor-1 (HBGF-1), also known as acidic fibroblast growth factor, is a potent mitogen for a variety of cell types including vascular endothelial and smooth muscle cells. Studies using murine 3T3 fibroblasts have shown that HBGF-1 induces numerous cellular responses such as the tyrosine phosphorylation of specific polypeptides and the increased expression of actin mRNA. Here we report that the addition of HBGF-1 to quiescent human umbilical vein endothelial cells increases the level of platelet-derived growth factor (PDGF) A-chain mRNA but not PDGF B-chain mRNA. In contrast, factors that inhibit endothelial cell proliferation such as phorbol myristate acetate and the cytokines interleukin-1, interleukin-6, and tumor necrosis factor-alpha increase both PDGF A-chain and B-chain mRNA levels. HBGF-1 induction of PDGF A-chain mRNA expression occurs in the presence of the protein synthesis inhibitor cycloheximide and thus does not require de novo protein synthesis. HBGF-1 also increases c-fos, c-jun, and c-myc mRNA levels; in the presence of cycloheximide, PDGF A-chain and protooncogene mRNA accumulation kinetics are similar. Nuclear run-on experiments indicate that the transcription rate of the PDGF A-chain gene transiently increases after HBGF-1 addition. Immunoprecipitation analysis using PDGF A-chain-specific antibodies indicates that HBGF-1-stimulated cells synthesize and secrete an increased amount of PDGF relative to unstimulated cells. If HBGF-1 can regulate PDGF expression by vascular endothelial cells in vivo, then HBGF-1 availability would be an important component of smooth muscle cell growth control. For example, HBGF-1 within the vessel wall would promote smooth muscle cell proliferation by (a) direct interaction with smooth muscle cell HBGF-1 receptors, and (b) increasing the amount of endothelial cell-derived PDGF available for binding to smooth muscle cell PDGF receptors.
Laboratory of Molecular Biology, Jerome H. Holland Laboratory for the Biomedical Sciences, American Red Cross, Rockville, Maryland 20855.
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Gay
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Winkles
D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D015342:DNA Probes; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016220:Fibroblast Growth Factor 1; D015870:Gene Expression / Q000187:drug effects*; D006133:Growth Substances / Q000494:pharmacology*; D006493:Heparin / Q000494:pharmacology*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D046911:Macromolecular Substances; D008934:Mitogens / Q000494:pharmacology*; D009693:Nucleic Acid Hybridization; D010982:Platelet-Derived Growth Factor / Q000235:genetics*; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D015183:Restriction Mapping; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014471:Umbilical Veins
D015342:DNA Probes; D006133:Growth Substances; D007375:Interleukin-1; D046911:Macromolecular Substances; D008934:Mitogens; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D011994:Recombinant Proteins; D016220:Fibroblast Growth Factor 1; D006493:Heparin; D004247:DNA; D013755:Tetradecanoylphorbol Acetate; D013936:Thymidine