Celecoxib restores angiogenic factor expression at the maternal-fetal interface in the BPH/5 mouse model of preeclampsia
Celecoxib restores angiogenic factor expression at the maternal-fetal interface in the BPH/5 mouse model of preeclampsia
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DOI：
10.1152/physiolgenomics.00115.2017
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发表时间：
2018-05-01
影响因子：
4.6
通讯作者：
Sones, Jenny L.
中科院分区：
文献类型：
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作者：
Reijnders, Dorien;Liu, Chin-Chi;Sones, Jenny L.
子痫前期（PE）是一种妊娠期高血压疾病。是胎儿和产妇发病/死亡的主要原因。胎盘内的早期血管生成和炎症紊乱被认为是母体PE综合征和不良妊娠结局发展的基础。然而，确切的病因仍然在很大程度上未知。在这里，我们使用BPH/5小鼠PE模型来阐明妊娠早期炎症导致母胎界面血管生成因子异常表达的方式。我们先前已经描述了使用抗炎性环氧合酶-2（Cox 2）特异性抑制剂塞来昔布治疗后，该模型中母体高血压和胎儿生长受限的改善。为了进一步描述塞来昔布改善BPH/5小鼠不良妊娠结局的机制，我们测定了塞来昔布治疗后血管生成因子和补体途径组分的表达。在BPH/5植入部位，缺氧诱导因子-1 α（Hif 1 α）、血红素加氧酶-1（Ho-1）和干细胞因子（Scf）mRNA升高，同时前列腺素合成酶2（Ptgs 2）（编码Cox 2）和VEGF蛋白升高。血管生成素1（Ang 1），图尼卡内膜内皮细胞激酶2受体（Tie 2）。补体因子3（C3）和补体因子B（CfB）在妊娠中期BPH/5胎盘中升高。而BPH/5的VEGF、Ang 1和Tie 2表达水平在塞来昔布治疗后正常化，胎盘C3和CfB mRNA保持不变。然而，塞来昔布确实降低了BPH/5小鼠妊娠中期的妊娠特异性循环可溶性fms样酪氨酸激酶-1（sFlt-1）升高。这些数据表明，在植入过程中升高的Cox 2导致BPH/5小鼠PE模型中胎盘血管生成因子失衡。
Preeclampsia (PE), a hypertensive disease of pregnancy. is a leading cause of fetal and maternal morbidity/mortality. Early angiogenic and inflammatory disturbances within the placenta are thought to underlie the development of the maternal PE syndrome and poor pregnancy outcomes. However, the exact etiology remains largely unknown. Here, we use the BPH/5 mouse model of PE to elucidate the way in which inflammation early in pregnancy contributes to abnormal expression of angiogenic factors at the maternal-fetal interface. We have previously described improvement in maternal hypertension and fetal growth restriction in this model after treatment with the anti-inflammatory cyclooxygenase-2 (Cox2) specific inhibitor celecoxib. To further characterize the mechanisms by which celecoxib improves poor pregnancy outcomes in BPH/5 mice, we determined expression of angiogenic factors and complement pathway components after celecoxib. In BPH/5 implantation sites there was increased hypoxia inducible factor-1 alpha (Hif1 alpha), heme oxygenase-1 (Ho-1), and stem cell factor (Scf) mRNA concomitant with elevated prostaglandin synthase 2 (Ptgs2), encoding Cox2, and elevated VEGF protein. Angiopoietin 1 (Ang1), tunica interna endothelial cell kinase-2 receptor (Tie2). complement factor 3 (C3), and complement factor B (CfB) were increased in midgestation BPH/5 placentae. Whereas BPH/5 expression levels of VEGF, Ang1, and Tie2 normalized after celecoxib, placental C3 and CfB mRNA remained unchanged. however, celecoxib did reduce the pregnancy-specific circulating soluble fms-like tyrosine kinase-1 (sFlt-1) rise in BPH/5 mice at midgestation. These data show that elevated Cox2 during implantation contributes to placental angiogenic factor imbalances in the BPH/5 mouse model of PE.