title: Deficiency in catechol-O-methyltransferase and 2-methoxyoestradiol is associated with pre-eclampsia.
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-1alpha 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.
authors.affiliation: Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Keizo
authors.initials: K
authors.lastname: Kanasaki
authors.forename: Kristin
authors.initials: K
authors.lastname: Palmsten
authors.forename: Hikaru
authors.initials: H
authors.lastname: Sugimoto
authors.forename: Shakil
authors.initials: S
authors.lastname: Ahmad
authors.forename: Yuki
authors.initials: Y
authors.lastname: Hamano
authors.forename: Liang
authors.initials: L
authors.lastname: Xie
authors.forename: Samuel
authors.initials: S
authors.lastname: Parry
authors.forename: Hellmut G
authors.initials: HG
authors.lastname: Augustin
authors.forename: Vincent H
authors.initials: VH
authors.lastname: Gattone
authors.forename: Judah
authors.initials: J
authors.lastname: Folkman
authors.forename: Jerome F
authors.initials: JF
authors.lastname: Strauss
authors.forename: Raghu
authors.initials: R
authors.lastname: Kalluri
mesh_terms: D000077584:2-Methoxyestradiol; D000418:Albumins / Q000032:analysis; D000818:Animals; D001794:Blood Pressure; D002394:Catechol O-Methyltransferase / Q000032:analysis / Q000172:deficiency* / Q000235:genetics; D003404:Creatinine / Q000652:urine; D004195:Disease Models, Animal; D004958:Estradiol / Q000031:analogs & derivatives* / Q000097:blood / Q000172:deficiency* / Q000652:urine; D005260:Female; D006801:Humans; D006973:Hypertension; D000860:Hypoxia / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology; D008098:Litter Size; D008297:Male; D051379:Mice; D010920:Placenta / Q000201:enzymology / Q000473:pathology; D011225:Pre-Eclampsia / Q000097:blood / Q000201:enzymology / Q000378:metabolism* / Q000652:urine; D011247:Pregnancy; D011507:Proteinuria; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000097:blood
chemical_list: D000418:Albumins; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D004958:Estradiol; D000077584:2-Methoxyestradiol; D003404:Creatinine; D002394:Catechol O-Methyltransferase; D040281:Vascular Endothelial Growth Factor Receptor-1