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dc.contributor.authorLee, Soo Bong
dc.contributor.authorWong, Amy P.
dc.contributor.authorKanasaki, Keizo
dc.contributor.authorXu, Yong
dc.contributor.authorShenoy, Vivek K.
dc.contributor.authorMcElrath, Thomas Frederick
dc.contributor.authorWhitesides, George McClelland
dc.contributor.authorKalluri, Raghu
dc.date.accessioned2017-07-24T18:13:10Z
dc.date.issued2010
dc.identifier.citationLee, Soo Bong, Amy P. Wong, Keizo Kanasaki, Yong Xu, Vivek K. Shenoy, Thomas F. McElrath, George M. Whitesides, and Raghu Kalluri. 2010. “Preeclampsia.” The American Journal of Pathology 176 (2) (February): 710–720. doi:10.2353/ajpath.2010.090513.en_US
dc.identifier.issn0002-9440en_US
dc.identifier.issn1525-2191en_US
dc.identifier.issn0002-9440en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:33490479
dc.description.abstractInadequate 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-1α (HIF-1α), transforming growth factor-β3 (TGF-β3), 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-1α, TGF-β3, 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-1α, TGF-β3, 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.en_US
dc.description.sponsorshipChemistry and Chemical Biologyen_US
dc.language.isoen_USen_US
dc.publisherElsevier BVen_US
dc.relation.isversionofdoi:10.2353/ajpath.2010.090513en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2808078/pdf/JPATH176000710.pdfen_US
dash.licenseMETA_ONLY
dc.titlePreeclampsiaen_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalThe American Journal of Pathologyen_US
dash.depositing.authorWhitesides, George McClelland
dash.embargo.until10000-01-01
dash.affiliation.otherObstetrics, Gynecology and Reproductive Biologyen_US
dc.identifier.doi10.2353/ajpath.2010.090513*
workflow.legacycommentsFAR 2011; file is a scan file.contents Whitesides emailed 2016-05-15 MM Whitesides emailed 2017-02-25 MM meta.darken_US
dash.contributor.affiliatedMcElrath, Thomas
dash.contributor.affiliatedKalluri, Raghu
dash.contributor.affiliatedWhitesides, George
dc.identifier.orcid0000-0001-9451-2442


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