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.
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Succinate is also an inhibitor of HIF-1α, which has been implicated in the exaggerated production of sFlt-1 and in the pathophysiology of preeclampsia.
“However, succinate is also an inhibitor of HIF-1α(213), which has been implicated in the exaggerated production of sFlt-1 and in the pathophysiology of preeclampsia(214, 215)”
From Metformin, the Aspirin of the 21st Century: Its Role in Gestational Diabetes Mellitus, Prevention of Preeclampsia and Cancer, and the Promotion of Longevity (2017) · cites this paper as [214]
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- Authors
- Kanasaki, K., Palmsten, K., Sugimoto, H., Ahmad, S., Hamano, Y., Xie, L., Parry, S., Augustin, H. G., Gattone, V. H., Folkman, J., Strauss, J. F., & Kalluri, R.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Birmingham Women's Hospital (GB)
- University of Pennsylvania (US)
- German Cancer Research Center (DE)
- Indiana University Indianapolis (US)
- Boston Children's Hospital (US)
- Virginia Commonwealth University (US)
- Corresponding author
- Kalluri, Raghu
- ORCID
- Venue
- Nature
- Published
- 2008-05-11
- Volume
- 453
- Issue
- 7198
- Pages
- 1117-1121
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2066278927
- Cited by
- 381
- References
- 34
- Citations by year
- 2026: 4 · 2025: 12 · 2024: 8 · 2023: 8 · 2022: 13 · 2021: 18 · 2020: 22 · 2019: 27 · 2018: 28 · 2017: 31 · 2016: 16 · 2015: 22 · 2014: 29 · 2013: 22 · 2012: 29
- FWCI
- 34.71
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Funders
- Beth Israel Deaconess Medical Center
- University of Pennsylvania
- British Heart Foundation
- Fondation pour la Recherche Médicale
- Georg-August-Universität Göttingen
- Kanae Foundation for the Promotion of Medical Science
- National Institutes of Health
- Medical Research Council
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 62987, DK61688, R01DK062987, DK 13193, DK-55001, R01DK061688, R01DK055001)
- Topics
- Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
- Health Sciences › Medicine › Psychiatry and Mental health › Neurological Complications and Syndromes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Eicosanoids and Hypertension Pharmacology
- Keywords
- preeclampsia, catechol-O-methyltransferase, 2-methoxyestradiol, placental hypoxia, angiogenic imbalance, soluble fms-like tyrosine kinase-1, vascular endothelial growth factor, placental growth factor, placenta, pregnancy complications, therapeutic target, proteinuria, hypertension, edema
- MeSH terms
- 2-Methoxyestradiol, Albumins, Animals, Hypoxia, Blood Pressure, Catechol O-Methyltransferase, Creatinine, Disease Models, Animal, Estradiol, Female, Humans, Hypertension, Killer Cells, Natural, Litter Size, Male, Placenta, Pre-Eclampsia, Pregnancy, Proteinuria, Vascular Endothelial Growth Factor Receptor-1, Mice, Hypoxia-Inducible Factor 1, alpha Subunit
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