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- Title
Deficiency in catechol-O-methyltransferase and 2-methoxyoestradiol is associated with pre-eclampsia.
- Authors
Kanasaki, Keizo; Palmsten, Kristin; Sugimoto, Hikaru; Ahmad, Shakil; Hamano, Yuki; Xie, Liang; Parry, Samuel; Augustin, Hellmut G.; Gattone, Vincent H.; Folkman, Judah; Strauss, Jerome F.; Kalluri, Raghu
- Abstract
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-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 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.
- Subjects
RISK factors of preeclampsia; ESTRADIOL; CATECHOL; PREECLAMPSIA; HYPOXEMIA
- Publication
Nature, 2008, Vol 453, Issue 7198, p1117
- ISSN
0028-0836
- Publication type
Article
- DOI
10.1038/nature06951