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-beta1.
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.
Alexakis
Catherine
C
CRRET/CNRS FRE 2412, Faculté des Sciences, Université de Paris 12, Créteil Cedex, France.
Mestries
Patricia
P
Garcia
Stéphanie
S
Petit
Emmanuel
E
Barbier
Véronique
V
Papy-Garcia
Dulce
D
Sagot
Marie-Astride
MA
Barritault
Denis
D
Caruelle
Jean Pierre
JP
Kern
Patrick
P
D000818:Animals; D001011:Aorta / Q000166:cytology; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D024042:Collagen Type I / Q000096:biosynthesis* / Q000235:genetics; D024061:Collagen Type III / Q000096:biosynthesis* / Q000235:genetics; D024062:Collagen Type V / Q000096:biosynthesis* / Q000235:genetics; D003911:Dextrans / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D016222:Fibroblast Growth Factor 2 / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006493:Heparin / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D009844:Oligosaccharides / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance; D034421:Sus scrofa; D016212:Transforming Growth Factor beta / Q000502:physiology*; D053773:Transforming Growth Factor beta1
D024042:Collagen Type I; D024061:Collagen Type III; D024062:Collagen Type V; D003911:Dextrans; D009844:Oligosaccharides; C431384:RG 1503; C475611:RG1192; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D016222:Fibroblast Growth Factor 2; D006493:Heparin