Generation and phenotypic analysis of protein S-deficient mice
Generation and phenotypic analysis of protein S-deficient mice
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DOI：
10.1182/blood-2009-03-209031
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发表时间：
2009-09-10
期刊：
影响因子：
20.3
通讯作者：
Angelillo-Scherrer, Anne
中科院分区：
文献类型：
--
作者：
Saller, Francois;Brisset, Anne C.;Angelillo-Scherrer, Anne
蛋白S（Protein S，PS）是一种重要的天然抗凝剂，具有多种潜在的生物学功能。为了进一步研究PS在体内的作用，我们产生了Pros（+/-）杂合小鼠。在无效（-）等位基因中，Pros外显子3至7已通过条件性基因靶向切除。Pros（+/-）小鼠未出现任何自发性血栓形成体征，在血浆凝血和凝血酶生成试验中PS血浆水平和活化蛋白C辅因子活性降低。不能证明PS的组织因子途径抑制物辅因子活性。在组织因子诱导的血栓栓塞模型中，杂合Pros（+/-）小鼠在体内表现出显著的血栓形成表型。通过Pros（+/-）亲本交配未获得存活的Pros（-/-）小鼠。发现大多数E17.5 Pros（-/-）胚胎死亡，伴有重度颅内出血，最可能表现为消耗性凝血病，如血管内和间质纤维蛋白沉积以及肝脏中巨核细胞数量增加所示，表明外周血小板减少症。少数E17.5 Pros（-/-）胚胎具有不太严重的表型，表明危及生命的表现可能发生在E17.5和足月之间。因此，与人类表型相似，小鼠轻度杂合PS缺陷与血栓形成表型相关，而PS完全纯合缺陷与生命不相容。（血。2009; 114：2307-2314）
Protein S (PS) is an important natural anticoagulant with potentially multiple biologic functions. To investigate further the role of PS in vivo, we generated Pros(+/-) heterozygous mice. In the null (-) allele, the Pros exons 3 to 7 have been excised through conditional gene targeting. Pros(+/-) mice did not present any signs of spontaneous thrombosis and had reduced PS plasma levels and activated protein C cofactor activity in plasma coagulation and thrombin generation assays. Tissue factor pathway inhibitor cofactor activity of PS could not be demonstrated. Heterozygous Pros(+/-) mice exhibited a notable thrombotic phenotype in vivo when challenged in a tissue factor-induced thromboembolism model. No viable Pros(-/-) mice were obtained through mating of Pros(+/-) parents. Most E17.5 Pros(-/-) embryos were found dead with severe intracranial hemorrhages and most likely presented consumptive coagulopathy, as demonstrated by intravascular and interstitial fibrin deposition and an increased number of megakaryocytes in the liver, suggesting peripheral thrombocytopenia. A few E17.5 Pros(-/-) embryos had less severe phenotype, indicating that life-threatening manifestations might occur between E17.5 and the full term. Thus, similar to human phenotypes, mild heterozygous PS deficiency in mice was associated with a thrombotic phenotype, whereas total homozygous deficiency in PS was incompatible with life. (Blood. 2009; 114: 2307-2314)