Specific RGTA increases collagen V expression by cultured aortic smooth muscle cells via activation and protection of transforming growth factor-beta1

Regenerating agents (RGTA) are defined as heparan sulfate mimics, which in vivo stimulate tissue repair. RGTA are obtained by controlled grafting of c arboxymethyl and sulfate groups on dextran polymers. RGTA are selected in v itro, on their ability to protect heparin binding growth factors such as TG F-beta1 for example, as well as to alter extracellular matrix biosynthesis. We had reported that RGTA were able to modulate smooth muscle cell (SMC) c ollagen biosynthesis. Here, we demonstrated that a specific RGTA (RG-1503), altered differentially collagen type expression by post-confluent SMC and that this action involves TGF-beta1. RG-1503 decreased, by 50%, collagen I and III biosynthesis and stimulated specifically, by twofold, collagen V bi osynthesis. TGF-beta1 stimulated collagen I and V by 1.5- and threefold, re spectively. A synergic action for RGTA in association with TGF-beta1 was ob served specifically for collagen V expression (eightfold increase). The sti mulation of collagen V biosynthesis by RGTA was abolished by TGF-beta1 neut ralizing antibodies. These modulations occurred at protein and mRNA levels. RG-1503 did not alter TGF-beta1 mRNA steady state level or total TGF-beta1 protein content (latent + active forms). However, RG-1503 significantly in duced an elevated proportion of active TGF-beta1 form, which could result f rom the selective protection from proteolytic degradation of TGF-beta1 by R G-1503. These data open a rationale for understanding the stimulation of ti ssue repair induced by RGTA, and also, a new insight for developing drugs a dapted to inhibit excess collagen deposition in smooth muscle cells associa ted vascular disorder, and in fibrotic diseases. (C) 2001 Elsevier Science B.V./International Society of Matrix Biology. All rights reserved.