| Preeclampsia: 2-methoxyestradiol induces cytotrophoblast invasion and vascular development specifically under hypoxic conditions. | |
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MedLine Citation:
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PMID: 20075204 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Soo Bong Lee; Amy P Wong; Keizo Kanasaki; Yong Xu; Vivek K Shenoy; Thomas F McElrath; George M Whitesides; Raghu Kalluri |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-01-14 |
Journal Detail:
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Title: The American journal of pathology Volume: 176 ISSN: 1525-2191 ISO Abbreviation: Am. J. Pathol. Publication Date: 2010 Feb |
Date Detail:
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Created Date: 2010-01-26 Completed Date: 2010-03-16 Revised Date: 2011-07-22 |
Medline Journal Info:
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Nlm Unique ID: 0370502 Medline TA: Am J Pathol Country: United States |
Other Details:
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Languages: eng Pagination: 710-20 Citation Subset: AIM; IM |
Affiliation:
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Division of Matrix Biology, CLS 11086, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Blood Vessels / drug effects*, growth & development Catechol O-Methyltransferase / genetics, metabolism Cell Adhesion / drug effects Cell Hypoxia / drug effects, genetics, physiology Cell Movement / drug effects Cells, Cultured Drug Synergism Estradiol / analogs & derivatives*, metabolism, pharmacology Female Humans Mice Mice, Knockout Neovascularization, Physiologic / drug effects*, genetics Oxygen / pharmacology* Pre-Eclampsia / etiology*, genetics, metabolism, pathology Pregnancy Trophoblasts / drug effects*, pathology, physiology |
| Grant Support | |
ID/Acronym/Agency:
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DK 55001/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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362-07-2/2-methoxyestradiol; 50-28-2/Estradiol; 7782-44-7/Oxygen; EC 2.1.1.6/Catechol O-Methyltransferase |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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