Structurally different RGTAs modulate collagen‐type expression by cultured aortic smooth muscle cells via different pathways involving fibroblast growth factor‐2 or transforming growth factor‐β1

Abstract

We have engineered polymers called ReGeneraTing Agents (RGTAs), which mimic the protecting and potentiating properties of heparan sulfates toward heparin-binding growth factors (HBGF). RGTAs have been shown to optimize cell growth and regulate collagen production in vitro. Here, we studied relationships between RGTA structure and collagen-type expression in aortic smooth muscle cells by using two RGTAs, the carboxylmethylsulfate dextran RG-1503 and the carboxylmethylsulfate dextran with added benzylamide RG-1192. RG-1192 specifically induced a fivefold decrease in collagen III synthesis. This effect was abolished by FGF-2 neutralizing antibody. RG-1192 and FGF-2 acted synergistically to decrease collagen III. RG-1192 was more effective than heparin in this process. RG-1192 increased the pericellular localization of FGF-2 and protected FGF-2 from proteolysis. Surface plasmon resonance analysis indicated a Kd of 15.7 nM for the RG-1192/FGF-2 interaction (10.6 nM for the heparin/FGF-2 interaction). The structurally different RG-1503 (without benzylamide) did not interact with FGF-2 and worked synergistically with TGF-beta1 to specifically induce a twofold increase in collagen V. RGTAs with different structures exert different modulating effects on the collagen phenotype. Selection of appropriate RGTAs, which had been shown to enhance in vivo tissue repair, may provide a mean of correcting collagen abnormalities in vascular disorders and more generally in fibrotic diseases.

RGTA OTR4120, a heparan sulfate mimetic, is a possible long‐term active agent to heal burned skin

“…These polymers are engineered and selected to express a low anticoagulant activity compared with heparin 23 while preserving the protecting and potentiating effects of heparin on heparin-binding growth factor activities. 17,32,33 The aim of this work was to evaluate the effect of the RGTA OTR4120 on the quality of matrix remodeling in an animal model of skin burn injury. In an Figure 6.…”

“…This specific effect of RGTA on collagen III synthesis has been previously described and could implicate that RGTA interfered with FGF-2 bioavailability. 17 Presence of a relative increase in collagen III is often associated with fibrosis and excessive scarring in many diseases. 12,[35][36][37] Antifibrotic effects of RGTA have been demonstrated in earlier studies.…”

“…39 Another possible explanation to the effects of OTR4120 lies in its ability to enhance the bioavailability of TGF-b1 and to interact specifically with this compound. 17,32 TGF-b1 is involved in the production and regeneration of ECM in normal and disease states and plays a pivotal role in collagen phenotype regulation by stimulating the production of both collagen I and collagen III. 40 Our study establishes that OTR4120 regulates the coexpression of collagen I and collagen III at cutaneous burn sites and suggests that this effect may involve a TGF-b1-related pathway.…”

“…RGTA induced ECM remodeling by decreasing the production of collagen III relative to other collagen types in smooth muscle cells. [17][18][19] In addition, RGTA restored a nearly normal pattern of collagen expression in biopsies from patients with Crohn's disease, specifically reducing the overexpression of collagen III by 75%. 13 Moreover, RGTA modulated the enzymatic activities of several proteases involved in ECM remodeling.…”

Insights on a new path of pre-mitochondrial apoptosis regulation by a glycosaminoglycan mimetic

“…[14][15][16][17] Therefore they were also named RGTA s for ReGeneraTing Agents. Here, we postulate that GAG-mimetics can participate to regulation of apoptosis in a mechanism implicating cathepsins activation and lysosomal membrane permeabilization.…”