Control of smooth muscle cell growth by components of the extracellular matrix: autocrine role for thrombospondin.
Addition of platelet-derived growth factor (PDGF) to growth-arrested cultured smooth muscle cells (SMC) induces the synthesis and secretion of thrombospondin (TS), a glycoprotein component of the SMC extracellular matrix in vitro. This induction occurs at PDGF concentrations that are suboptimal for a mitogenic response. In this study we examined the effect of TS on the proliferation of SMC, using a serum-free mitogenesis assay. Addition of either epidermal growth factor (EGF) or purified human platelet TS to quiescent rat vascular SMC did not substantially stimulate mitogenesis; the 30-hr nuclear labeling index increased from a mean of 7% in control cells to 20% for EGF-treated SMC and 17% for cells exposed to TS alone. However, TS and EGF acted synergistically to stimulate DNA synthesis by SMC, increasing the labeling index to 47%. The facilitative effect of TS on EGF-mediated mitogenesis was inhibited by heparin, a known inhibitor of SMC growth and migration that also blocks incorporation of TS into the SMC extracellular matrix. The effect was specific for EGF; TS did not augment the response of cells to insulin or insulin-like growth factor 1. These data establish a functional role for cell-derived TS and provide evidence for the presence of an autocrine, growth-supportive mechanism involving the extracellular matrix. In addition, our experiments support the existence of a novel, heparin-sensitive SMC mitogenic pathway and suggest a mechanism whereby heparin-like molecules may inhibit SMC proliferation.
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects*; D002478:Cells, Cultured; D004357:Drug Synergism; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D005109:Extracellular Matrix / Q000502:physiology*; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006131:Growth Inhibitors; D006133:Growth Substances; D006493:Heparin / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D051381:Rats; D019699:Thrombospondins
D006023:Glycoproteins; D006131:Growth Inhibitors; D006133:Growth Substances; D019699:Thrombospondins; D004815:Epidermal Growth Factor; D006493:Heparin