GROWTH-FACTOR AND CYTOKINE-REGULATED HYALURONAN-BINDING PROTEIN TSG-6IS LOCALIZED TO THE INJURY-INDUCED RAT NEOINTIMA AND CONFERS ENHANCEDGROWTH IN VASCULAR SMOOTH-MUSCLE CELLS

Hyaluronan (HA) and HA-binding proteins have been implicated in a dive rse array of biological processes, including development, tissue repai r, and tumor invasion. However, the role of HA and HA-binding proteins in atherosclerosis and restenosis is poorly understood. PS4 (TSG-6) i s a HA-binding protein expressed by cultured vascular smooth muscle ce lls (SMCs) in response to serum and growth factor stimulation. To deli neate a possible role for TSG-6 in vascular disease progression, we ha ve characterized its expression in cultured SMCs and in a rat vascular injury model, and we have studied the effect of constitutive overexpr ession of TSG-6 on SMC behavior. We found that interleukin-1 (IL-1) bu t not tumor necrosis factor or interleukin-6 was able to stimulate TSG -6 expression in SMCs. The IL-1 pathway could be distinguished from th e growth factor pathway by its insensitivity to protein synthesis inhi bitors. Furthermore, epidermal growth factor, fibroblast growth factor -1, and transforming growth factor-beta 1 were all capable of augmenti ng maximum IL-1-induced expression of TSG-6. To gain further insight i nto the function of TSG-6 in SMCs, we examined the effect of constitut ive overexpression of TSG-6 on these cells, We found that TSG-6-overex pressing cells grew >50% faster than control cells. Furthermore, this growth advantage became more evident in the absence of serum growth fa ctors, with an average increase in cell number of 118% over control ce lls after 6 days. Consistent with these in vitro data, we observed int ense immunostaining for TSG-6 in proliferating SMCs in the rat neointi ma after injury, whereas only an occasional cell was positive for TSG- 6 in the medial layer and in nonballooned arteries. We conclude that t he expression of TSG-6 is tightly controlled by growth factors and cyt okines via two distinct pathways in SMCs and that overexpression of TS G-6 confers a growth advantage to these cells.