Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA.
Blood. 2010 Sep 9;116(10):1787-94. doi: 10.1182/blood-2009-10-250910. Epub 2010 Jun 1.
The antithrombotic surface of endothelium is regulated in a coordinated manner. Tissue factor pathway inhibitor (TFPI) localized at the endothelial cell surface regulates the production of FXa by inhibiting the TF/VIIa complex. Systemic homozygotic deletion of the first Kunitz (K1) domain of TFPI results in intrauterine lethality in mice. Here we define the cellular sources of TFPI and their role in development, hemostasis, and thrombosis using TFPI conditional knockout mice. We used a Cre-lox strategy and generated mice with a floxed exon 4 (TFPI(Flox)) which encodes for the TFPI-K1 domain. Mice bred into Tie2-Cre and LysM-Cre lines to delete TFPI-K1 in endothelial (TFPI(Tie2)) and myelomonocytic (TFPI(LysM)) cells resulted in viable and fertile offspring. Plasma TFPI activity was reduced in the TFPI(Tie2) (71% ± 0.9%, P < .001) and TFPI(LysM) (19% ± 0.6%, P < .001) compared with TFPI(Flox) littermate controls. Tail and cuticle bleeding were unaffected. However, TFPI(Tie2) mice but not TFPI(LysM) mice had increased ferric chloride-induced arterial thrombosis. Taken together, the data reveal distinct roles for endothelial- and myelomonocytic-derived TFPI.
内皮细胞的抗血栓表面是协调调节的。组织因子途径抑制剂（TFPI）定位于内皮细胞表面，通过抑制 TF/VIIa 复合物来调节 FXa 的产生。TFPI 的第一个 Kunitz（K1）结构域的全身性纯合缺失导致小鼠宫内致死。在这里，我们使用 TFPI 条件性敲除小鼠来定义 TFPI 的细胞来源及其在发育、止血和血栓形成中的作用。我们使用 Cre-lox 策略生成了一个 TFPI(Flox)的 floxed 外显子 4（编码 TFPI-K1 结构域）的小鼠。将这些小鼠繁殖到 Tie2-Cre 和 LysM-Cre 系中，以敲除内皮细胞（TFPI(Tie2))和髓系细胞（TFPI(LysM))中的 TFPI-K1，得到了存活且可育的后代。与 TFPI(Flox)同窝仔相比，TFPI(Tie2)（71%±0.9%，P<.001）和 TFPI(LysM)（19%±0.6%，P<.001）的血浆 TFPI 活性降低。尾巴和表皮出血不受影响。然而，只有 TFPI(Tie2)小鼠而不是 TFPI(LysM)小鼠的氯化铁诱导的动脉血栓形成增加。总之，这些数据揭示了内皮细胞和髓系细胞衍生的 TFPI 的不同作用。
