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: 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
• Journal: Nature (Nature) Vol. 453 Issue 7198 Pg. 1117-21 (Jun 19 2008) ISSN: 1476-4687 [Electronic] England
• PMID: 18469803 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Albumins
• Hif1a protein, mouse
• Hypoxia-Inducible Factor 1, alpha Subunit
• Estradiol
• 2-Methoxyestradiol
• Creatinine
• Catechol O-Methyltransferase
• Vascular Endothelial Growth Factor Receptor-1

Topics

• 2-Methoxyestradiol
• Albumins (analysis)
• Animals
• Blood Pressure
• Catechol O-Methyltransferase (analysis, deficiency, genetics)
• Creatinine (urine)
• Disease Models, Animal
• Estradiol (analogs & derivatives, blood, deficiency, urine)
• Female
• Humans
• Hypertension
• Hypoxia (metabolism)
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Killer Cells, Natural (immunology)
• Litter Size
• Male
• Mice
• Placenta (enzymology, pathology)
• Pre-Eclampsia (blood, enzymology, metabolism, urine)
• Pregnancy
• Proteinuria
• Vascular Endothelial Growth Factor Receptor-1 (blood)