Atherosclerotic Human Vessels Expression , Localization , and Activity of Tissue Factor Pathway Inhibitor in Normal and
Atherosclerotic Human Vessels Expression , Localization , and Activity of Tissue Factor Pathway Inhibitor in Normal and
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发表时间：
2000
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通讯作者：
J. Crawley;F. Lupu;A. Westmuckett;N. Severs;V. Kakkar;C. Lupu
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作者：
J. Crawley;F. Lupu;A. Westmuckett;N. Severs;V. Kakkar;C. Lupu
组织因子（TF）途径抑制剂（TFPI）是TF-因子VIIa（FVIIa）复合物（TFz FVII）促凝血活性的主要下调因子。动脉粥样硬化血管壁中存在的活性TF被认为是原发性动脉粥样硬化的主要并发症，即斑块破裂后急性血栓形成的原因，但我们对TF相关的TFPI表达位点的了解仍然是零碎的。本研究的目的是研究TFPI在正常血管壁和动脉粥样硬化血管壁中的表达、定位和活性及其与TF活性和分布的关系。我们采用了一种新的方法，其中连续的横截面的人血管段被用来进行一套完整的测定：免疫标记的TFPI和/或TF，原位杂交的表达TFPI mRNA，ELISA的TFPI抗原的测定，和功能测定的TFPI和TF的活性。在健康血管中，TFPI蛋白和mRNA存在于管腔和微血管内皮细胞（EC）和中膜平滑肌细胞（SMC）中。在动脉粥样硬化血管中，TFPI蛋白和mRNA经常与TF共定位于覆盖斑块的EC和微血管中，以及中膜和新生内膜SMC中，以及坏死核心周围区域的巨噬细胞和T细胞中。在超微结构水平上，免疫金电子显微镜证实TFPI在EC、巨噬细胞/泡沫细胞和SMC中的定位。在内皮细胞和平滑肌细胞中，金颗粒装饰于质膜和质膜小窝。酶联免疫吸附试验显示动脉粥样硬化组织中TFPI含量高于健康血管。TFPI对TF z FVIIa诱导的凝血具有功能活性，并且其活性在显示较少TF的那些组织中更高。TFPI和TF在复杂斑块中的表达量最高。免疫荧光显示，TFPI与机化血栓内的血小板和纤维蛋白富集区共定位。动脉粥样硬化血管切片促进因子X的活化，这取决于TF的存在，并通过用抗TFPI IgG预孵育切片来增强。总之，我们的研究结果表明，TFPI主要表达在正常血管壁和增强在动脉粥样硬化血管，在某种程度上表明TF PI在TF活性的调节中的重要作用。（Arterioscler ThrombVasc Biol . 2000;20：1362-1373）。
Tissue factor (TF) pathway inhibitor (TFPI) is the major downregulator of the procoagulant activity of the TF–factor VIIa (FVIIa) complex (TFz FVII). The active TF present in the atherosclerotic vessel wall is proposed to be responsible for the major complication of primary atherosclerosis, namely, acute thrombosis after plaque rupture, but our knowledge of the sites of TFPI expression in relation to TF remains fragmentary. The aim of this study was to investigate the expression, localization, and activity of TFPI and its relation to the activity and distribution of TF in the normal and atherosclerotic vessel wall. We applied a novel approach in which serial cross sections of human vascular segments were used to perform a complete set of assays: immunolabeling for TFPI and/or TF, in situ hybridization for the expression of TFPI mRNA, ELISA for the determination of TFPI antigen, and functional assay for the activity of TFPI and TF. In healthy vessels, TFPI protein and mRNA are present in luminal and microvascular endothelial cells (ECs) and in the medial smooth muscle cells (SMCs). In atherosclerotic vessels, TFPI protein and mRNA frequently colocalized with TF in ECs overlying the plaque and in microvessels, as well as in the medial and neointimal SMCs, and in macrophages and T cells in areas surrounding the necrotic core. At the ultrastructural level, immunogold electron microscopy confirmed the localization of TFPI in ECs, macrophages/foam cells, and SMCs. In ECs and SMCs, the gold particles decorated the plasmalemma proper and the caveolae. ELISA on cross sections revealed that atherosclerotic tissues contain more TFPI than do the healthy vessels. TFPI was functionally active against TF z FVIIa-induced coagulation, and its activity was higher in those tissues that display less TF. The largest amount of TFPI and TF were detected in complicated arterial plaques. By immunofluorescence, TFPI colocalized with plateletand fibrin-rich areas within the organized thrombi. Atherosclerotic vessel sections promote activation of factor X, which is dependent on the presence of TF and enhanced by preincubation of the sections with anti-TFPI IgG. Taken altogether, our results suggest that TFPI is largely expressed in the normal vessel wall and enhanced in the atherosclerotic vessel, in a manner suggesting a significant role of TFPI in the regulation of TF activity. (Arterioscler Thromb Vasc Biol . 2000;20:1362-1373.)