Tissue factor pathway inhibitor overexpression inhibits hypoxia-induced pulmonary hypertension.
Tissue factor pathway inhibitor overexpression inhibits hypoxia-induced pulmonary hypertension.
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DOI：
10.1165/rcmb.2009-0144oc
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发表时间：
2010-07
影响因子：
6.4
通讯作者：
T. White;T. Witt;Shuchong Pan;C. Mueske;L. Kleppe;Eric W. Holroyd;H. Champion;R. Simari
中科院分区：
文献类型：
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作者：
T. White;T. Witt;Shuchong Pan;C. Mueske;L. Kleppe;Eric W. Holroyd;H. Champion;R. Simari
肺动脉高压（PH）是慢性呼吸系统疾病的常见并发症。血管收缩增强、肺血管重塑和原位血栓形成导致与缺氧性肺疾病相关的PH中观察到的肺血管阻力增加。组织因子途径调节纤维蛋白沉积对急性和慢性血管损伤的反应。我们假设组织因子途径的抑制将导致通常与缺氧诱导的PH相关的病理生理参数的衰减。我们使用慢性缺氧诱导的PH小鼠模型，使用通过平滑肌特异性启动子SM22（TFPI（SM22））过表达组织因子途径抑制剂（TFPI）的小鼠来测试这一假设。与野生型（WT）小鼠相比，TFPI（SM22）小鼠具有增加的肺TFPI表达。在WT小鼠中，暴露于慢性缺氧（在10%O（2）中28天）导致右心室收缩压和平均肺动脉压增加，TFPI（SM22）小鼠的变化显著减少。慢性缺氧还导致WT小鼠中显著的肺血管肌化，其在TFPI（SM22）小鼠中显著减少。考虑到TFPI的多效性效应，考虑了这些血流动力学效应的自分泌和旁分泌机制。在暴露于缺氧后3天，TFPI（SM22）小鼠的肺纤维蛋白沉积少于WT小鼠，这与TFPI的抗血栓形成作用一致。此外，与WT小鼠相比，TFPI（SM22）小鼠的增殖（增殖细胞核抗原阳性）肺血管平滑肌细胞数量显著减少，这与体外结果一致。这些研究结果表明，TFPI过表达的结果在改善血液动力学性能和减少肺血管重塑的小鼠模型缺氧诱导的PH。这种改善部分是由于TFPI过表达的自分泌和旁分泌作用。
Pulmonary hypertension (PH) is a commonly recognized complication of chronic respiratory disease. Enhanced vasoconstriction, pulmonary vascular remodeling, and in situ thrombosis contribute to the increased pulmonary vascular resistance observed in PH associated with hypoxic lung disease. The tissue factor pathway regulates fibrin deposition in response to acute and chronic vascular injury. We hypothesized that inhibition of the tissue factor pathway would result in attenuation of pathophysiologic parameters typically associated with hypoxia-induced PH. We tested this hypothesis using a chronic hypoxia-induced murine model of PH using mice that overexpress tissue factor pathway inhibitor (TFPI) via the smooth muscle-specific promoter SM22 (TFPI(SM22)). TFPI(SM22) mice have increased pulmonary TFPI expression compared with wild-type (WT) mice. In WT mice, exposure to chronic hypoxia (28 d at 10% O(2)) resulted in increased systolic right ventricular and mean pulmonary arterial pressures, changes that were significantly reduced in TFPI(SM22) mice. Chronic hypoxia also resulted in significant pulmonary vascular muscularization in WT mice, which was significantly reduced in TFPI(SM22) mice. Given the pleiotropic effects of TFPI, autocrine and paracrine mechanisms for these hemodynamic effects were considered. TFPI(SM22) mice had less pulmonary fibrin deposition than WT mice at 3 days after exposure to hypoxia, which is consistent with the antithrombotic effects of TFPI. Additionally, TFPI(SM22) mice had a significant reduction in the number of proliferating (proliferating cell nuclear antigen positive) pulmonary vascular smooth muscle cells compared with WT mice, which is consistent with in vitro findings. These findings demonstrate that overexpression of TFPI results in improved hemodynamic performance and reduced pulmonary vascular remodeling in a murine model of hypoxia-induced PH. This improvement is in part due to the autocrine and paracrine effects of TFPI overexpression.