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.

Endothelial Nitric Oxide Synthase Deficiency Reduces Uterine Blood Flow, Spiral Artery Elongation, and Placental Oxygenation in Pregnant Mice

“…14 In the normal mouse placenta, we found that pimonidazole staining was highest in the spongiotrophoblast and trophoblast giant cell layers of the junctional zone, confirming previous results. 34,35 This region is primarily perfused by maternal blood in venous channels draining the labyrinthine sinusoids of the placenta. 36 This blood is depleted of nutrients and oxygen and enriched in wastes from the fetus, which may explain why this region is relatively hypoxic.…”

Maternal Vascular Physiology in Preeclampsia

“…100 Increased receptor-mediated uterine artery constriction has been also reported in models with experimental preeclampsia. Uterine arteries from the catechol-O-methyl transferase (COMT −/− ) knockout mouse 101,102 and the TgA rat (transgenic human angiotensinogen × human renin) exhibited augmented uterine artery responsiveness to phenylephrine and angiotensin II, respectively. 9 Reactivity to agonist-induced vasodilation in the main uterine artery relies primarily on NO, although PGI 2 contribution has been reported.…”

Plasma level of hydroxysteroid (17-β) dehydrogenase 1 in the second trimester is an independent risk factor for predicting preeclampsia after adjusting for the effects of mean blood pressure, bilateral notching and plasma level of soluble fms-like tyrosine kinase 1/placental growth factor ratio

“…17b-Estradiol is converted to hydroxyestradiol by the action of cytochrome P450, and hydroxyestradiol is converted to 2-methoxyestradiol by the action of catechol-O-methyltransferase (COMT). 29,30 The decrease of 2-methoxyestradiol by the deficient of COMT induced the PE-like phenotype via the decrease of 2-methoxyestradiol in mice, 29,30 indicating that some derivatives of estradiol might be implicated in the genesis of PE. Several studies of polymorphisms of estrogen receptor gene also suggested the possible implication of estrogen for the genesis of PE.…”