Sulfated glycosaminoglycan derivatives affect the bioactivity of angiogenic growth factors

Abstract

Event Abstract Back to Event Sulfated glycosaminoglycan derivatives affect the bioactivity of angiogenic growth factors Linda Koehler1, Sandra Rother1, Stephanie Moeller2, Matthias Schnabelrauch2, Vera Hintze1 and Dieter Scharnweber1 1 TU Dresden, Max Bergmann Center of Biomaterials, Germany 2 INNOVENT e.V., Biomaterials Department, Germany Introduction: Sulfated glycosaminoglycans (GAGs) are promising candidates for functional bio­ma­terials since their sulfate groups modulate the binding of growth factors, thereby influencing their biological activity profile. The interaction of different GAGs with several growth factors has previously been reported. These stu­dies demonstrated a sulfation- and carbohydrate backbone-dependent binding of GAGs resulting in an influence on the interaction of these mediators with recep­tors and therefore their bioactivity[1],[2]. Angiogenic growth factors, like vascular endothelial (VEGF) and basic fibroblast growth factor (bFGF) play an important role during wound healing[3],[4]. Heparin is known to distinctly regulate VEGF and bFGF signaling by altering their interaction with the respective receptors[4],[5]. Hence we hypothesize that VEGF and bFGF interaction with different GAGs influences their bioactivity depending on their degree of sul­fa­tion (D.S.) and carbohydrate backbone. This might lead to important implications for the use of GAGs as part of biomaterials for controlling angiogenesis during wound healing in health com­pro­mised patients. Materials and Methods: The interaction of VEGF and bFGF with different sulfated hyaluronan (sHA) and chondroitin sulfate (CS) derivatives was determined via surface plasmon resonance (SPR). VEGF or bFGF were im­mobilized onto a sensor chip surface and dif­fe­rent concentrations of solute GAGs were injected to reveal their binding strength. Addi­tionally, ELISA experiments with immobilized GAGs were performed to validate the SPR results. The influence of GAGs on the capability of growth factors to bind to their receptors was again investigated by SPR, while the consequences of the GAG/growth factor interaction on bioactivity were studied in cell-based bioassays. Here pre-incubated GAG/growth factor complexes were added to the cells and growth factor-stimulated cell proliferation was de­termined. Results and Discussion: In case of bFGF the binding strength of sHA and CS derivatives reveals a strong dependence on the D.S. but not on the carbohydrate backbone of the GAG. For VEGF, however, low-sHA and high-sulfated CS showed a comparable bin­ding strength. These results imply that the different molecular geometries in the carbohydrate backbone of the GAGs might render the respec­tive sulfate groups to interact differently. This is further emphasized in investigations with TGF-β1 whe­re naturally sulfated heparin demonstrated a comparable binding strength to high sulfated CS, even though it has a lower D.S[2]. The binding of growth factors to their respective recep­tors was modulated in the presence of GAGs which implies an altered biological profile. This could be verified in cell-based bioassays, since the presence of GAGs affected the growth factor-stimulated proliferation of the cells. Conclusion: The results imply that sulfated GAGs are promising candidates to be included in biomaterial coatings for controlling angiogenesis and therefore wound hea­ling processes, which would in particular be beneficial for health com­pro­mised patients. We acknowledge financial support by the DFG [SFB Transregio 67, projects A2, A3 and Z3].