title: Preeclampsia: 2-methoxyestradiol induces cytotrophoblast invasion and vascular development specifically under hypoxic conditions.
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.
authors.affiliation: Division of Matrix Biology, CLS 11086, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Soo Bong
authors.initials: SB
authors.lastname: Lee
authors.forename: Amy P
authors.initials: AP
authors.lastname: Wong
authors.forename: Keizo
authors.initials: K
authors.lastname: Kanasaki
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.forename: Vivek K
authors.initials: VK
authors.lastname: Shenoy
authors.forename: Thomas F
authors.initials: TF
authors.lastname: McElrath
authors.forename: George M
authors.initials: GM
authors.lastname: Whitesides
authors.forename: Raghu
authors.initials: R
authors.lastname: Kalluri
mesh_terms: D000077584:2-Methoxyestradiol; D000818:Animals; D001808:Blood Vessels / Q000187:drug effects* / Q000254:growth & development; D002394:Catechol O-Methyltransferase / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004357:Drug Synergism; D004958:Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000235:genetics; D010100:Oxygen / Q000494:pharmacology*; D011225:Pre-Eclampsia / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D014327:Trophoblasts / Q000187:drug effects* / Q000473:pathology / Q000502:physiology
chemical_list: D004958:Estradiol; D000077584:2-Methoxyestradiol; D002394:Catechol O-Methyltransferase; D010100:Oxygen