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.

Keywords: 2-methoxyestradiol (2-ME); aromatase; hypoxia; methionine–homocysteine metabolism; preeclampsia.

Figure 1.

Invasion process scheme during early normal and abnormal pregnancy. A, In normal placentation, EVCT cells derived from proliferating cytotrophoblast invade the maternal decidua and differentiate into interstitial and endovascular trophoblast cells. This process involves critical metabolic pathways necessary for adequate EVCT invasion. During interstitial invasion, the compact decidual tissue is “swamped” by interstitial EVCT cells that cluster around blood vessels and in the inner third myometrium zone of the placenta. At the same time, endovascular trophoblast cells migrate into the maternal spiral arteries in order to replace the maternal endothelial lining as far as the inner third of the myometrium, degrading the muscular and elastic component of the vessel walls. This results in the formation of low-resistance vessels that are required for the establishment of the definitive uteroplacental circulation and for adequate fetal growth, as can be seen in normal pregnancy. B, Alterations in one or more of the critical metabolic pathways involved in the normal invasive process (eg, prolonged hypoxia during invasion process; low 2-ME levels at implantation time due to alteration in COMT enzyme activity, SAM/SAH levels, and/or MHM pathway alteration; 17β-estradiol level alteration due to an aromatase pathway alteration; angiogenic or matrix remodeling imbalance) may result in a reduction of uteroplacental flow due to deficient trophoblast invasion and failure of the maternal spiral arteries to undergo vascular remodeling. This could trigger other local alterations during the second trimester of pregnancy that ultimately contribute to the development of PE. EVCT indicates extravillous cytotrophoblast; PE, preeclampsia; 2-ME, 2-methoxyestradiol; COMT, catechol-O-methyltransferase; HIF-1α, hypoxia-inducible factor-1α; TGF-β3, transforming growing factor-β3; MHM, methionine–homocysteine metabolism; TIMP, tissue inhibitor of metalloproteinases; MMP, matrix metalloproteinases.

Figure 2.

Methionine–homocysteine and aromatase pathways and their involvement in 2-ME synthesis. A, The THF obtained through diet, produces methionine through the remethylation pathway (where MTHFR, MTRR, and MTR are involved) which when added to the diet-supplemented methionine, generates SAM, the main methyl group donor in the methylation reaction. The COMT is a SAM-dependent enzyme that catalyzes the conversion of 2-hydroxyestradiol into 2-ME. B, Androstenedione and testosterone are converted into estrone and 17β-estradiol, respectively, through the action of aromatase. 17β-Estradiol is converted by CyP450 into 2-hydroxyestradiol, the substrate used by COMT for the synthesis of 2-ME. Low levels of 2-ME observed in patients with PE could be explained, among others, by (1) the decreased expression/activity of the COMT enzyme; (2) a decrease in the bioavailability of SAM, likely due to alterations in the methionine–homocysteine pathway that reduce the availability of methionine and SAM, or increase levels of homocysteine and SAH; (3) a decrease in the bioavailability of 17β-estradiol likely due to an alteration in the aromatase pathway. THF indicates tetrahydrofolate; MTHFR, methylenetetrahydrofolate reductase; MTR, methionine synthase; MTRR, methionine synthase reductase; Vit B₁₂, vitamin B₁₂; SAM, S-adenosylmethionine; SAH, S-adenosythomocysteine; 2-ME, 2-methoxyestradiol; PE, preeclampsia; CyP450, cytochromeP450.