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.
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.
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DOI：
10.1021/acsami.7b01300
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发表时间：
2017-03
影响因子：
9.5
通讯作者：
S. Rother;Sergey A. Samsonov;S. Moeller;M. Schnabelrauch;J. Rademann;Joanna Blaszkiewicz;Sebastian Köhling;J. Waltenberger;M. T. Pisabarro;D. Scharnweber;V. Hintze
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文献类型：
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作者：
S. Rother;Sergey A. Samsonov;S. Moeller;M. Schnabelrauch;J. Rademann;Joanna Blaszkiewicz;Sebastian Köhling;J. Waltenberger;M. T. Pisabarro;D. Scharnweber;V. Hintze
一些病理条件，如类风湿性关节炎，眼部新生血管形成，癌症，动脉粥样硬化往往与异常血管生成，这需要创新的生物材料为基础的治疗方案，以控制血管生成因子的活性。在这里，我们研究了硫酸化透明质酸（sHA）和过硫酸化硫酸软骨素衍生物作为功能性生物材料的潜在成分如何在体外调节血管内皮生长因子-A（VEGF-A）信号传导和内皮细胞活性。金属蛋白酶组织抑制剂-3（TIMP-3）是一种有效的血管生成抑制剂，通过与VEGF-A竞争结合VEGF受体-2（VEGFR-2）发挥其活性。然而，尽管已知TIMP-3和VEGF-A与糖胺聚糖（GAG）相互作用，但GAG改变VEGF-A/TIMP-3调节的VEGFR-2信号传导的潜在作用和机制仍不清楚。结合表面等离子体共振，免疫生物化学分析和分子建模，我们证明了VEGF-A和TIMP-3与sHA包被的表面的同时结合，并确定了一种新的机制，硫酸化GAG衍生物通过该机制控制血管生成：GAG衍生物阻断VEGF-A和TIMP-3与VEGFR-2的结合，从而以确定的硫酸依赖性方式降低其生物活性。这种作用对于硫酸化GAG衍生物比对于天然GAG更强。TIMP-3/sHA复合物的同时形成部分地挽救了sHA抑制的VEGF-A/VEGFR-2信号传导和内皮细胞活化。这些结果为GAG衍生物调节血管生成因子提供了新的见解，并突出了sHA衍生物治疗与VEGF-A和VEGFR-2水平升高相关的疾病的潜力。
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.