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 tyrosine kinase-1 (sFLT-1, the soluble form of VEGF receptor 1) might contribute to some of the maternal symptoms of pre-eclampsia1,2,3,4,5. 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 levels5,6. Moreover, recent experiments strongly suggest that several soluble factors affecting the vasculature are probably elevated because of placental hypoxia in the pre-eclamptic 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-1α 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.
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We dedicate this manuscript to Judah Folkman for his inspiration and guidance. We thank P. T. Männistö for providing us with information about the Comt-/- mice. Beth Israel Deaconess Medical Center has licensed technologies associated with 2-ME/COMT and preeclampsia to Cynthus, Inc. This work was supported primarily by the BIDMC Department of Medicine research funds to the Division of Matrix Biology, and partly supported by National Institutes of Health grants DK 55001, DK 62987, DK 13193 and DK 61688. S.A. was supported by grants from the British Heart Foundation and the Medical Research Council. K.K. was partly supported by Foreign Study Grants from the Kanae Foundation for the Promotion of Medical Science in Japan.
Author Contributions K.K. performed all the experiments, analysed the data and participated in manuscript writing. K.P., H.S., Y.H. and L.X. performed some of the experiments. V.H.G. performed the EM analysis. S.P., S.A. and H.G.A. provided samples. J.F.S. provided samples and contributed to manuscript writing. J.F. made intellectual contributions. R.K. conceived the project, designed the experimental approach, made intellectual contributions and wrote the manuscript.
The file contains Supplementary Figures 1-15 with Legends, Supplementary Table 1 with patient information, Supplementary Discussion and Supplementary Notes with additional references. (PDF 18859 kb)
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Kanasaki, K., Palmsten, K., Sugimoto, H. et al. Deficiency in catechol-O-methyltransferase and 2-methoxyoestradiol is associated with pre-eclampsia. Nature 453, 1117–1121 (2008). https://doi.org/10.1038/nature06951
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