Metabolic Pathways Involved in 2-Methoxyestradiol Synthesis and Their Role in Preeclampsia

Abstract

Preeclampsia (PE) remains a major cause of maternal/fetal morbidity-mortality worldwide. The first stage of PE is characterized by placental hypoxia due to a relative reduction in uteroplacental blood flow, resulting from restricted trophoblast invasion. However, hypoxia is also an essential element for the success of invasion. Under hypoxic conditions, 2-methoxyestradiol (2-ME) could induce the differentiation of cytotrophoblast cells into an invasive phenotype in culture. 2-Methoxyestradiol is generated by catechol-O-methyltransferase, an enzyme involved in the metabolic pathway of estrogens. During pregnancy, circulating 2-ME levels increase significantly when compared to the menstrual cycle. Interestingly, plasma levels of 2-ME are lower in women with PE than in controls, and these differences are apparent weeks or even months before the clinical manifestations of the disease. This article reviews the metabolic pathways involved in 2-ME synthesis and discusses the roles of these pathways in normal and abnormal pregnancies, with particular emphasis on PE.

G protein-coupled receptor 30 regulates trophoblast invasion and its deficiency is associated with preeclampsia

“…In addition, the circulating level of an estrogen metabolite, 2-methoxyestradiol (2-ME), is significantly upregulated in normal pregnant women, as compared with nonpregnant women. However, plasma levels of 2-ME are significantly reduced in women with preeclampsia [35]. This is consistent with animal studies that demonstrated that a deficiency in catechol-O-methyl transferase, and a subsequent reduction in 2-ME concentration, resulted in the development of preeclampsia-like signs [36].…”

Serum markers of pre‐eclampsia identified on proteomics

“…Consequently, the transformation of spiral arteries is suppressed, and instead of high‐resistance, low‐flow vessels, they are transformed into dilated vessels . The decreased blood flow and fetoplacental perfusion induce placental ischemia, producing the subsequent oxidative stress and angiogenic imbalance that contribute to the development of endothelial dysfunction in the later gestation period of PE patients . In the present study, JEG‐3 cell invasion ability increased with elevated RBP4 concentration.…”

Levels of Key Enzymes of Methionine-Homocysteine Metabolism in Preeclampsia

“…With COMT being responsible for methylating 2-Hydroxyestradiol (2-HE) into 2-ME, it has been proposed that the low activity or expression of this enzyme could be involved in the pathogenesis of PE. The normal expression of COMT in placentae of patients with PE [11] and the conflicting results regarding the presence of SNPs that may reduce the activity of this enzyme in these patients [10] force us to search other explanations [12]. The Methionine-homocysteine metabolism (MHM), the process responsible for supplying COMT with the methyl group necessary for 2-ME synthesis, could be an alternative if it is somehow altered, being unable to supply enough methyl groups to sustain adequate concentrations of 2-ME.…”