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Deficiency in catechol-O-methyltransferase and 2-methoxyoestradiol is associated with pre-eclampsia

机译：儿茶酚-O-甲基转移酶和2-甲氧基雌二醇的不足与先兆子痫有关

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Despite intense investigation, mechanisms that facilitate the emergence of the pre-eclampsia phenotype in women are still unknown. Placental hypoxia, hypertension, proteinuria and oedema are the principal clinical features of this disease. It is speculated that hypoxia-driven disruption of the angiogenic balance involving vascular endothelial growth factor (VEGF)/ placenta-derived growth factor (PLGF) and soluble Fms-like tyro-sine kinase-1 (sFLT-1, the soluble form of VEGF receptor 1) might contribute to some of the maternal symptoms of pre-eclampsia. However, pre-eclampsia does not develop in all women with high sFLT-1 or low PLGF levels, and it also occurs in some women with low sFLT-1 and high PLGF levels. Moreover, recent experiments strongly suggest that several soluble factors affecting the vascula-ture are probably elevated because of placental hypoxia in the pre-edamptic women, indicating that upstream molecular defect(s) may contribute to pre-eclampsia. Here we show that pregnant mice deficient in catechol-O-methyltransferase (COMT) show a pre-eclampsia-like phenotype resulting from an absence of 2-methoxyoestradiol (2-ME), a natural metabolite of oestradiol that is elevated during the third trimester of normal human pregnancy. 2-ME ameliorates all pre-eclampsia-like features without toxicity in the Comt~(-/-) pregnant mice and suppresses placental hypoxia, hypoxia-inducible factor-lα expression and sFLT-1 elevation. The levels of COMT and 2-ME are significantly lower in women with severe pre-eclampsia. Our studies identify a genetic mouse model for pre-eclampsia and suggest that 2-ME may have utility as a plasma and urine diagnostic marker for this disease, and may also serve as a therapeutic supplement to prevent or treat this disorder.
机译：尽管进行了深入的研究，促进女性先兆子痫表型出现的机制仍然未知。胎盘缺氧，高血压，蛋白尿和水肿是该病的主要临床特征。据推测，缺氧引起的血管生成平衡的破坏涉及血管内皮生长因子（VEGF）/胎盘来源的生长因子（PLGF）和可溶性Fms样酪氨酸激酶1（sFLT-1，VEGF的可溶性形式）受体1）可能会导致先兆子痫的一些孕妇症状。然而，子痫前期并非在所有sFLT-1高或PLGF低的女性中发展，它也发生在某些sFLT-1低和PLGF高的女性中。此外，最近的实验有力地表明，由于水浸前妇女的胎盘缺氧，影响血管的几种可溶性因子可能升高，表明上游分子缺陷可能导致先兆子痫。在这里，我们显示缺乏儿茶酚-O-甲基转移酶（COMT）的怀孕小鼠表现出先兆子痫样表型，这是由于缺少2-甲氧基雌二醇（2-ME）（一种雌二醇的天然代谢产物，在孕晚期会升高）正常人怀孕。 2-ME改善了Comt〜（-/-）怀孕小鼠的所有先兆子痫样特征，但无毒性，并抑制了胎盘缺氧，缺氧诱导因子-1α表达和sFLT-1升高。患有严重先兆子痫的女性的COMT和2-ME水平显着降低。我们的研究确定了先兆子痫的遗传小鼠模型，并表明2-ME可以作为该疾病的血浆和尿液诊断标志物，还可以用作预防或治疗该疾病的治疗补充剂。

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  • 来源
    《Nature》 |2008年第7198期|1117-1121|共5页
  • 作者

    Keizo Kanasaki; Kristin Palmsten; Hikaru Sugimoto; Shakil Ahmad; Yuki Hamano; Liang Xie; Samuel Parry; Hellmut G. Augustin; Vincent H. Gattone Jr; Judah Folkman; Jerome F. Strauss; Raghu Kalluri;

  • 作者单位

    Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA;

    Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA;

    Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA;

    Departments of Reproductive and Vascular Biology Institute of Biomedical Research, The Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK Birmingham Women's Hospital, Edgbaston, Birmingham B15 2TG, UK;

    Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA;

    Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA;

    Department of Obstetrics and Gynecology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6142, USA;

    Joint Research Division Vascular Biology, Medical Faculty Mannheim, University of Heidelberg, and German Cancer Research Center Heidelberg, 69120 Heidelberg, Germany;

    Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA;

    Program in Vascular Biology, Department of Surgical Research, The Children's Hospital Boston, Boston, Massachusetts 02215, USA;

    School of Medicine, Virginia Commonwealth University, Richmond, Virginia 23298, USA;

    Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Boston, Massachusetts 02215, USA Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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