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

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

Research output: Contribution to journalLetter

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.
Original languageEnglish
Pages (from-to)1117-1121
Number of pages5
JournalNature
Volume453
Issue number7198
Early online date11 May 2008
DOIs
Publication statusPublished - 8 Jun 2008

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Catechol O-Methyltransferase
Pre-Eclampsia
Vascular Endothelial Growth Factor Receptor-1
Phenotype
methylcobalamin-coenzyme M methyltransferase
2-methoxyestradiol
Genetic Models
Third Pregnancy Trimester
Proteinuria
Vascular Endothelial Growth Factor A
Estradiol
Edema
Mothers
Hypoxia
Urine
Hypertension
Pregnancy

Cite this

Kanasaki, K., Palmsten, K., Sugimoto, H., Ahmad, S., Hamano, Y., Xie, L., ... Kalluri, R. (2008). Deficiency in catechol-O-methyltransferase and 2-methoxyoestradiol is associated with pre-eclampsia. Nature, 453(7198), 1117-1121. https://doi.org/10.1038/nature06951
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. / Deficiency in catechol-O-methyltransferase and 2-methoxyoestradiol is associated with pre-eclampsia. In: Nature. 2008 ; Vol. 453, No. 7198. pp. 1117-1121.
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Kanasaki, K, Palmsten, K, Sugimoto, H, Ahmad, S, Hamano, Y, Xie, L, Parry, S, Augustin, HG, Gattone, VH, Folkman, J, Strauss, JF & Kalluri, R 2008, 'Deficiency in catechol-O-methyltransferase and 2-methoxyoestradiol is associated with pre-eclampsia', Nature, vol. 453, no. 7198, pp. 1117-1121. https://doi.org/10.1038/nature06951

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

In: Nature, Vol. 453, No. 7198, 08.06.2008, p. 1117-1121.

Research output: Contribution to journalLetter

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T1 - Deficiency in catechol-O-methyltransferase and 2-methoxyoestradiol is associated with pre-eclampsia

AU - Kanasaki, Keizo

AU - Palmsten, Kristin

AU - Sugimoto, Hikaru

AU - Ahmad, Shakil

AU - Hamano, Yuki

AU - Xie, Liang

AU - Parry, Samuel

AU - Augustin, Hellmut G.

AU - Gattone, Vincent H.

AU - Folkman, Judah

AU - Strauss, Jerome F.

AU - Kalluri, Raghu

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Y1 - 2008/6/8

N2 - 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.

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