Wodicka James R, Chambers Andrea M, Sangha Gurneet S, Goergen Craig J, Panitch Alyssa
Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, USA.
Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Pharmaceuticals (Basel). 2017 Mar 29;10(2):36. doi: 10.3390/ph10020036.
Endothelial cell (EC) dysfunction is associated with many disease states including deep vein thrombosis (DVT), chronic kidney disease, sepsis and diabetes. Loss of the glycocalyx, a thin glycosaminoglycan (GAG)-rich layer on the EC surface, is a key feature of endothelial dysfunction and increases exposure of EC adhesion molecules such as selectins, which are involved in platelet binding to ECs. Once bound, platelets cause thrombus formation and an increased inflammatory response. We have developed a GAG derived, selectin targeting anti-adhesive coating (termed EC-SEAL) consisting of a dermatan sulfate backbone and multiple selectin-binding peptides designed to bind to inflamed endothelium and prevent platelet binding to create a more quiescent endothelial state. Multiple EC-SEAL variants were evaluated and the lead variant was found to preferentially bind to selectin-expressing ECs and smooth muscle cells (SMCs) and inhibit platelet binding and activation in a dose-dependent manner. In an in vivo model of DVT, treatment with the lead variant resulted in reduced thrombus formation. These results indicate that EC-SEAL has promise as a potential therapeutic in the treatment of endothelial dysfunction.
内皮细胞（EC）功能障碍与许多疾病状态相关，包括深静脉血栓形成（DVT）、慢性肾病、败血症和糖尿病。糖萼是内皮细胞表面富含糖胺聚糖（GAG）的薄层，其丧失是内皮功能障碍的关键特征，并增加了内皮细胞粘附分子（如选择素）的暴露，这些分子参与血小板与内皮细胞的结合。一旦结合，血小板就会导致血栓形成并增加炎症反应。我们开发了一种源自GAG、靶向选择素的抗粘附涂层（称为EC-SEAL），它由硫酸皮肤素主链和多个选择素结合肽组成，旨在与炎症内皮结合并防止血小板结合，从而创造更静止的内皮状态。对多个EC-SEAL变体进行了评估，发现先导变体优先结合表达选择素的内皮细胞和平滑肌细胞（SMC），并以剂量依赖方式抑制血小板结合和激活。在DVT的体内模型中，用先导变体治疗可减少血栓形成。这些结果表明，EC-SEAL有望成为治疗内皮功能障碍的潜在疗法。
