title: Sulfated Hyaluronan Alters Endothelial Cell Activation in Vitro by Controlling the Biological Activity of the Angiogenic Factors Vascular Endothelial Growth Factor-A and Tissue Inhibitor of Metalloproteinase-3.
abstract: Several pathologic conditions such as rheumatoid arthritis, ocular neovascularization, cancer, or atherosclerosis are often associated with abnormal angiogenesis, which requires innovative biomaterial-based treatment options to control the activity of angiogenic factors. Here, we studied how sulfated hyaluronan (sHA) and oversulfated chondroitin sulfate derivatives as potential components of functional biomaterials modulate vascular endothelial growth factor-A (VEGF-A) signaling and endothelial cell activity in vitro. Tissue inhibitor of metalloproteinase-3 (TIMP-3), an effective angiogenesis inhibitor, exerts its activity by competing with VEGF-A for binding to VEGF receptor-2 (VEGFR-2). However, even though TIMP-3 and VEGF-A are known to interact with glycosaminoglycans (GAGs), the potential role and mechanism by which GAGs alter the VEGF-A/TIMP-3 regulated VEGFR-2 signaling remains unclear. Combining surface plasmon resonance, immunobiochemical analysis, and molecular modeling, we demonstrate the simultaneous binding of VEGF-A and TIMP-3 to sHA-coated surfaces and identified a novel mechanism by which sulfated GAG derivatives control angiogenesis: GAG derivatives block the binding of VEGF-A and TIMP-3 to VEGFR-2 thereby reducing their biological activity in a defined, sulfation-dependent manner. This effect was stronger for sulfated GAG derivatives than for native GAGs. The simultaneous formation of TIMP-3/sHA complexes partially rescues the sHA inhibited VEGF-A/VEGFR-2 signaling and endothelial cell activation. These results provide novel insights into the regulation of angiogenic factors by GAG derivatives and highlight the potential of sHA derivatives for the treatment of diseases associated with increased VEGF-A and VEGFR-2 levels.
authors.affiliation: Institute of Materials Science, Max Bergmann Center of Biomaterials, Technische Universität Dresden , 01069 Dresden, Germany.
authors.forename: Sandra
authors.identifier: http://orcid.org/0000-0003-0631-752X
authors.initials: S
authors.lastname: Rother
authors.affiliation: Structural Bioinformatics, BIOTEC Technische Universität Dresden , Tatzberg 47-51, 01307 Dresden, Germany.
authors.forename: Sergey A
authors.initials: SA
authors.lastname: Samsonov
authors.affiliation: Biomaterials Department, INNOVENT e.V. , 07745 Jena, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Moeller
authors.affiliation: Biomaterials Department, INNOVENT e.V. , 07745 Jena, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schnabelrauch
authors.affiliation: Institute of Pharmacy & Institute of Chemistry and Biochemistry, Freie Universität Berlin , Königin-Luise-Strasse 2, 14195 Berlin, Germany.|Institute of Medical Physics and Biophysics, Universität Leipzig , Härtelstrasse 16/18, 04107 Leipzig, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Rademann
authors.affiliation: Institute of Pharmacy & Institute of Chemistry and Biochemistry, Freie Universität Berlin , Königin-Luise-Strasse 2, 14195 Berlin, Germany.|Institute of Medical Physics and Biophysics, Universität Leipzig , Härtelstrasse 16/18, 04107 Leipzig, Germany.
authors.forename: Joanna
authors.initials: J
authors.lastname: Blaszkiewicz
authors.affiliation: Institute of Pharmacy & Institute of Chemistry and Biochemistry, Freie Universität Berlin , Königin-Luise-Strasse 2, 14195 Berlin, Germany.|Institute of Medical Physics and Biophysics, Universität Leipzig , Härtelstrasse 16/18, 04107 Leipzig, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Köhling
authors.affiliation: Department of Cardiovascular Medicine, University of Münster , Albert-Schweitzer-Campus 1, 48149 Münster, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Waltenberger
authors.affiliation: Structural Bioinformatics, BIOTEC Technische Universität Dresden , Tatzberg 47-51, 01307 Dresden, Germany.
authors.forename: M Teresa
authors.initials: MT
authors.lastname: Pisabarro
authors.affiliation: Institute of Materials Science, Max Bergmann Center of Biomaterials, Technische Universität Dresden , 01069 Dresden, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Scharnweber
authors.affiliation: Institute of Materials Science, Max Bergmann Center of Biomaterials, Technische Universität Dresden , 01069 Dresden, Germany.
authors.forename: Vera
authors.initials: V
authors.lastname: Hintze
mesh_terms: D043925:Angiogenesis Inducing Agents; D042783:Endothelial Cells; D006820:Hyaluronic Acid / Q000737:chemistry*; D009389:Neovascularization, Pathologic; D019717:Tissue Inhibitor of Metalloproteinase-3; D042461:Vascular Endothelial Growth Factor A
chemical_list: D043925:Angiogenesis Inducing Agents; D019717:Tissue Inhibitor of Metalloproteinase-3; D042461:Vascular Endothelial Growth Factor A; D006820:Hyaluronic Acid
keywords: endothelial cells; glycosaminoglycans; hyaluronan/sulfated hyaluronan; tissue inhibitor of metalloproteinase-3; vascular endothelial growth factor-A