CHEMICALLY-MODIFIED DEXTRANS MODULATE EXPRESSION OF COLLAGEN PHENOTYPE BY CULTURED SMOOTH-MUSCLE CELLS IN RELATION TO THE DEGREE OF CARBOXYMETHYL, BENZYLAMIDE, AND SULFATION SUBSTITUTIONS

We developed regenerating agents (RGTAs) corresponding to polysacchari des derived from dextran and containing defined amounts of carboxymeth yl (CM), carboxymethyl sulfate (CMS), carboxymethyl benzylamine (CMB), or carboxymethyl benzylamide sulfate (CMBS) groups with varying degre es of substitution. These compounds mimicked some effects of heparin o n smooth muscle cell (SMC) proliferation and promoted in vivo tissue r emodeling. We demonstrated that only RGTAs containing both CM and sulf ate groups decreased SMC proliferation, in correlation with increased sulfation level. This effect was amplified by the presence of benzylam ide. Independent of this activity on cell proliferation (i.e., with po stconfluent cells), RGTAs modulated collagen biosynthesis by SMCs. On the one hand, CMBS more than CMS RGTAs induced a decrease of collagen Ill synthesis at the level of mRNA steady state and protein production . On the other hand, CMS to a greater extent than CMBS RGTAs increased both collagen V mRNA and protein production. In addition, only benzyl amide-containing RGTAs increased accumulation of collagen I and III in the cell lever. In conclusion, RGTA bioactivities required the presen ce of CM functions, increased with the sulfation level, and varied wit h benzylamide substitution. RGTAs that modulate cell proliferation and collagen biosynthesis by differential mechanisms may represent potent ial antifibrotic agents. (C) 1998 John Wiley & Sons, Inc.