A balance between tissue factor and tissue factor pathway inhibitor is required for embryonic development and hemostasis in adult mice
A balance between tissue factor and tissue factor pathway inhibitor is required for embryonic development and hemostasis in adult mice
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DOI：
10.1182/blood-2004-09-3724
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发表时间：
2005-04-01
期刊：
影响因子：
20.3
通讯作者：
Mackman, N
中科院分区：
文献类型：
--
作者：
Pedersen, B;Holscher, T;Mackman, N
小鼠组织因子(TF)基因或组织因子途径抑制物(TFPI)基因失活会导致胚胎死亡，表明两者都是胚胎发育所必需的。我们已经证明，表达低水平的转基因转铁蛋白(HTF)可以挽救Tf缺失的胚胎。然而，低转铁率小鼠(MTF(-/-)/HTF(+))在子宫、胎盘、心脏和肺有止血缺陷。在这项研究中，我们假设TFPI/-胚胎的死亡是由于未调控的Tf/FVIIa活性，而低Tf小鼠的止血缺陷是由于Tf表达不足所致。因此，我们试图通过降低TFPI的表达来挽救TFPI-/-胚胎，并通过取消TFPI的表达来恢复低TfI小鼠的止血。TFPI+/-/MTF(+/-)/HTF(+/-)杂交小鼠在断奶年龄从128只后代中产生了接近预期数量的TFPI-/-/Low-Tf小鼠，这表明TFPI-/-胚胎从胚胎死亡中拯救出来。相反，TFPI水平的降低呈剂量依赖性地延长低Tf小鼠的存活时间，并挽救肺和胎盘的出血缺陷，但不能挽救心脏或子宫的出血缺陷。这些结果表明，在胚胎发育期间和成年小鼠中，不同器官中TF和TFPI之间的正确平衡是维持止血所必需的。
Inactivation of the murine tissue factor (TF) gene or tissue factor pathway inhibitor 1 (TFPI) gene results in embryonic lethality, indicating that both are required for embryonic development. We have shown that expression of low levels of TF from a transgene (hTF) rescues TF-null embryos. However, low-TF mice (mTF(-/-)/ hTF(+)) have hemostatic defects in the uterus, placenta, heart, and lung. In this study, we hypothesized that the death of TFPI-/- embryos was due to unregulated TF/FVIIa activity and that the hemostatic defects in low-TF mice were due to insufficient TF expression. Therefore, we attempted to rescue TFPI-/- embryos by reducing TF expression, and to restore hemostasis in low-TF mice by abolishing TFPI expression. Intercrossing TFPI+/-/ mTF(+/-)/hTF(+/-) mice generated close to the expected number of TFPI-/-/low-TF mice at weaning age from 128 offspring, indicating rescue of TFPI-/- embryos from embryonic lethality. Conversely, a decrease in TFPI levels dose-dependently prolonged the survival of low-TF mice and rescued the hemorrhagic defects in the lung and placenta but not in the heart or uterus. These results indicate that the correct balance between TF and TFPI in different organs is required to maintain hemostasis during embryonic development and in adult mice.