Document Detail

Preeclampsia: 2-methoxyestradiol induces cytotrophoblast invasion and vascular development specifically under hypoxic conditions.
MedLine Citation:
PMID:  20075204     Owner:  NLM     Status:  MEDLINE    
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.
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:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-01-14
Journal Detail:
Title:  The American journal of pathology     Volume:  176     ISSN:  1525-2191     ISO Abbreviation:  Am. J. Pathol.     Publication Date:  2010 Feb 
Date Detail:
Created Date:  2010-01-26     Completed Date:  2010-03-16     Revised Date:  2011-07-22    
Medline Journal Info:
Nlm Unique ID:  0370502     Medline TA:  Am J Pathol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  710-20     Citation Subset:  AIM; IM    
Division of Matrix Biology, CLS 11086, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
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MeSH Terms
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
Mice, Knockout
Neovascularization, Physiologic / drug effects*,  genetics
Oxygen / pharmacology*
Pre-Eclampsia / etiology*,  genetics,  metabolism,  pathology
Trophoblasts / drug effects*,  pathology,  physiology
Grant Support
Reg. No./Substance:
362-07-2/2-methoxyestradiol; 50-28-2/Estradiol; 7782-44-7/Oxygen; EC O-Methyltransferase

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