Preeclampsia

Abstract

Inadequate invasion of the uterus by cytotrophoblasts is speculated to result in pregnancy-induced disorders such as preeclampsia. However, the molecular mechanisms that govern appropriate invasion of cytotrophoblasts are unknown. Here, we demonstrate that under low-oxygen conditions (2.5% oxygen), 2-methoxyestradiol (2-ME), which is a metabolite of estradiol and is generated by catechol-o-methyltransferase (COMT), induces invasion of cytotrophoblasts into a naturally-derived, extracellular matrix. Neither low-oxygen conditions nor 2-ME alone induces the invasion of cytotrophoblasts in this system; however, low-oxygen conditions combined with 2-ME result in the appropriate invasion of cytotrophoblasts into the extracellular matrix. Cytotrophoblast invasion under these conditions is also associated with a decrease in the expression of hypoxia-inducible factor-1alpha (HIF-1alpha), transforming growth factor-beta3 (TGF-beta3), and tissue inhibitor of metalloproteinases-2 (TIMP-2). Pregnant COMT-deficient mice with hypoxic placentas and preeclampsia-like features demonstrate an up-regulation of HIF-1alpha, TGF-beta3, and TIMP-2 when compared with wild-type mice; normal levels are restored on administration of 2-ME, which also results in the resolution of preeclampsia-like features in these mice. Indeed, placentas from patients with preeclampsia reveal lower levels of COMT and higher levels of HIF-1alpha, TGF-beta3, and TIMP-2 when compared with those from normal pregnant women. We demonstrate that low-oxygen conditions of the placenta are a critical co-stimulator along with 2-ME for the proper invasion of cytotrophoblasts to facilitate appropriate vascular development and oxygenation during pregnancy.

Adaptive mechanisms controlling uterine spiral artery remodeling during the establishment of pregnancy

“…Two examples will be discussed. Experimental evidence has accumulated suggesting that catechol-O-methyltransferase (COMT) and corin serine peptidase (CORIN) are modulators of trophoblast cell invasion and disrupted in preeclampsia (Kanasaki et al 2008; Lee et al 2010; Cui et al 2012). Their potential involvement in the etiology of the pregnancy-associated disease surfaced from examination of tissues from preeclamptic patients and has been bolstered through phenotypic investigations of genetically modified rodent models.…”

“…COMT is expressed in the placenta and methylates several circulating hormones, including catechol estrogens, and is responsible for the generation of 2-methoxyestradiol (2-ME). 2-ME synergizes with hypoxia to promote trophoblast cell invasive properties ( Lee et al 2010 ). Preeclamptic patients exhibit decreased placental COMT activities and disruption of the Comt gene in the mouse is associated with a preeclampsia-like phenotype in pregnant mice ( Kanasaki et al 2008 ).…”

Decreased Maternal Serum 2-Methoxyestradiol Levels are Associated with the Development of Preeclampsia

“…Until now, little has been known about the effects of 2-ME on the trophoblast cells proliferation and migration. Only one study reported that under 2.5% O 2 , but not 17% O 2 , 2-ME at 500 nM concentration significantly induced HTR-8/SVneo cells migration [6]. Our current study demonstrated that under 20% O 2 but not 2.5% O 2 , 2-ME suppressed HTR-8/SVneo cells proliferation, and 2-ME enhanced HTR-8/SVneo cells migratory ability under 2.5% O 2 in vitro , suggesting that oxygen environment is a pivotal determinants on trophoblast function [33].…”

“…Recent evidence has demonstrated that 2-ME under low-oxygen conditions is critical for the proper cytotrophoblast invasion, placental vascular development and regulation of oxygen tension during normal pregnancy; therefore, impaired 2-ME synthesis/release has been implicated in the etiopathogenesis of PE [2,5,6]. In support of this concept, Kanasaki et al has also reported that COMT-deficient mice exhibit a PE-like phenotype and placental hypoxia in pregnancy [7], and such PE-like features could be rescued by subcutaneous injection of 2-ME, further confirming the major roles of COMT/2-ME interactions in PE.…”

“…2-methoxyestradiol (2-ME) is a natural metabolite of 17β-estradiol, which is generated by catechol- O -methyltransferase (COMT) [6,7,8,9] This enzyme is widely distributed in many mammalian tissues including liver, kidney, brain and placenta [10,11]. Recent evidence has demonstrated that 2-ME under low-oxygen conditions is critical for the proper cytotrophoblast invasion, placental vascular development and regulation of oxygen tension during normal pregnancy; therefore, impaired 2-ME synthesis/release has been implicated in the etiopathogenesis of PE [2,5,6].…”