© 1997 American Heart Association, Inc.
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Growth Factor and Cytokine-Regulated Hyaluronan-Binding Protein TSG-6 Is Localized to the Injury-Induced Rat Neointima and Confers Enhanced Growth in Vascular Smooth Muscle Cells
From the Department of Molecular Biology (L.Y., R.M., N.A., G.L.) and Experimental Pathology (C.C.H.), Jerome H. Holland Laboratory, American Red Cross, Rockville, Md, and the Department of Anatomy and Cell Biology (G.L.), The George Washington University Medical Center, Washington, DC.
Correspondence to Dr Gene Liau, Department of Molecular Biology, Holland Laboratory, 15601 Crabbs Branch Way, Rockville, MD 20855. E-mail Liau{at}usa.redcross.org
Abstract Hyaluronan (HA) and HA-binding proteins have been implicated in a diverse array of biological processes, including development, tissue repair, and tumor invasion. However, the role of HA and HA-binding proteins in atherosclerosis and restenosis is poorly understood. PS4 (TSG-6) is a HA-binding protein expressed by cultured vascular smooth muscle cells (SMCs) in response to serum and growth factor stimulation. To delineate a possible role for TSG-6 in vascular disease progression, we have characterized its expression in cultured SMCs and in a rat vascular injury model, and we have studied the effect of constitutive overexpression of TSG-6 on SMC behavior. We found that interleukin-1 (IL-1) but not tumor necrosis factor or interleukin-6 was able to stimulate TSG-6 expression in SMCs. The IL-1 pathway could be distinguished from the growth factor pathway by its insensitivity to protein synthesis inhibitors. Furthermore, epidermal growth factor, fibroblast growth factor-1, and transforming growth factor-ß1 were all capable of augmenting maximum IL-1–induced expression of TSG-6. To gain further insight into the function of TSG-6 in SMCs, we examined the effect of constitutive overexpression of TSG-6 on these cells. We found that TSG-6–overexpressing cells grew >50% faster than control cells. Furthermore, this growth advantage became more evident in the absence of serum growth factors, with an average increase in cell number of 118% over control cells after 6 days. Consistent with these in vitro data, we observed intense immunostaining for TSG-6 in proliferating SMCs in the rat neointima after injury, whereas only an occasional cell was positive for TSG-6 in the medial layer and in nonballooned arteries. We conclude that the expression of TSG-6 is tightly controlled by growth factors and cytokines via two distinct pathways in SMCs and that overexpression of TSG-6 confers a growth advantage to these cells.
Key Words: hyaluronan • smooth muscle cell • extracellular matrix • cell proliferation • restenosis
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