Targeting FVIII expression to endothelial cells regenerates a releasable pool of FVIII and restores hemostasis in a mouse model of hemophilia A
Targeting FVIII expression to endothelial cells regenerates a releasable pool of FVIII and restores hemostasis in a mouse model of hemophilia A
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DOI：
10.1182/blood-2010-03-272419
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发表时间：
2010-10-21
期刊：
影响因子：
20.3
通讯作者：
Montgomery, Robert R.
中科院分区：
文献类型：
--
作者：
Shi, Qizhen;Fahs, Scot A.;Montgomery, Robert R.
合成因子VIII （FVIII）并将其释放到血液循环中的天然细胞类型仍不确定。体外研究表明，在内皮细胞中人工表达FVIII可产生细胞内FVIII池，FVIII可与其载体蛋白血管性血液病因子（VWF）一起被激动剂动员。在本研究中，我们发现在缺乏FVIII的小鼠血管内皮中表达人b结构域缺失的FVIII （hFVIII）会导致内皮细胞韦贝尔-帕拉体中FVIII和VWF的共同储存，并恢复血浆中FVIII的正常水平和活性。储存的FVIII通过皮下注射肾上腺素被动员到循环中。人血浆中FVIII活性严格依赖于VWF的存在。内皮特异性表达的hFVIII挽救了缺乏内源性FVIII的血友病小鼠的出血能力。内皮细胞衍生的hFVIII的止血功能在抗fviii抑制抗体的存在下被抑制。这些结果表明，在血友病a中，将FVIII的表达靶向内皮细胞可以建立一个可释放的FVIII池，并使血浆FVIII的水平和活性正常化，但并不能阻止抗FVIII抗体对转基因源性FVIII止血功能的抑制作用，正如血小板源性FVIII表达所见。[血液，2010;116(16):3049-3057]
The natural cell type(s) that synthesize and release factor VIII (FVIII) into the circulation are still not known with certainty. In vitro studies indicate that artificial expression of FVIII in endothelial cells produces an intracellular pool of FVIII that can be mobilized together with its carrier protein, von Willebrand factor (VWF), by agonists. Here, we show that expression of human B-domain deleted FVIII (hFVIII) in the vascular endothelium of otherwise FVIII-deficient mice results in costorage of FVIII and VWF in endothelial Weibel-Palade bodies and restores normal levels and activity of FVIII in plasma. Stored FVIII was mobilized into the circulation by subcutaneous administration of epinephrine. Human FVIII activity in plasma was strictly dependent on the presence of VWF. Endothelial-specific expression of hFVIII rescued the bleeding diathesis of hemophilic mice lacking endogenous FVIII. This hemostatic function of endothelial cell-derived hFVIII was suppressed in the presence of anti-FVIII inhibitory antibodies. These results suggest that targeting FVIII expression to endothelial cells may establish a releasable pool of FVIII and normalize plasma FVIII level and activity in hemophilia A, but does not prevent the inhibitory effect of anti-FVIII antibodies on the hemostatic function of transgene-derived hFVIII as is seen with platelet-derived FVIII expression. (Blood. 2010;116(16): 3049-3057)