title: Effects of reduced Gcm1 expression on trophoblast morphology, fetoplacental vascularity, and pregnancy outcomes in mice.
abstract: Preeclampsia is a life-threatening disorder characterized by maternal gestational hypertension and proteinuria that results from placental dysfunction. Placental abnormalities include abnormal syncytiotrophoblast and a 50% reduction in placental expression of the transcription factor Gcm1. In mice, homozygous deletion of Gcm1 prevents syncytiotrophoblast differentiation and is embryonic lethal. We used heterozygous Gcm1 mutants (Gcm1(+/-)) to test the hypothesis that hypomorphic expression of placental Gcm1 causes defective syncytiotrophoblast differentiation and maternal and placental phenotypes that resemble preeclampsia. We mated wild-type female mice with Gcm1(+/-) fathers to obtain wild-type mothers carrying ≈50% Gcm1(+/-) conceptuses. Gcm1(+/-) placentas had syncytiotrophoblast abnormalities including reduced gene expression of Gcm1-regulated SynB, elevated expression of sFlt1, a thickened interhemal membrane separating maternal and fetal circulations, and electron microscopic evidence in syncytiotrophoblast of necrosis and impaired maternal-fetal transfer. Fetoplacental vascularity was quantified by histomorphometry and microcomputed tomography imaging. In Gcm1(+/-), it was ≈30% greater than wild-type littermates, whereas placental vascular endothelial growth factor A (Vegfa) expression and fetal and placental weights did not differ. Wild-type mothers carrying Gcm1(+/-) conceptuses developed late gestational hypertension (118±2 versus 109.6±0.7 mm Hg in controls; P<0.05). We next correlated fetoplacental vascularity with placental Gcm1 expression in human control and pathological pregnancies and found that, as in mice, fetoplacental vascularity increased when GCM1 protein expression decreased (R(2)=-0.45; P<0.05). These results support a role for reduced placental Gcm1 expression as a causative factor in defective syncytiotrophoblast differentiation and maternal and placental phenotypes in preeclampsia in humans.
authors.affiliation: Faculty of Health Sciences, University of Ottawa, Ottawa, Ontario, Canada. shannon.bainbridge@uottawa.ca
authors.forename: Shannon A
authors.initials: SA
authors.lastname: Bainbridge
authors.forename: Abhijeet
authors.initials: A
authors.lastname: Minhas
authors.forename: Kathie J
authors.initials: KJ
authors.lastname: Whiteley
authors.forename: Dawei
authors.initials: D
authors.lastname: Qu
authors.forename: John G
authors.initials: JG
authors.lastname: Sled
authors.forename: John C P
authors.initials: JC
authors.lastname: Kingdom
authors.forename: S Lee
authors.initials: SL
authors.lastname: Adamson
mesh_terms: D000818:Animals; D004247:DNA / Q000235:genetics; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D005260:Female; D005333:Fetus / Q000098:blood supply* / Q000378:metabolism; D005786:Gene Expression Regulation; D005865:Gestational Age; D006801:Humans; D008297:Male; D051379:Mice; D009479:Neuropeptides / Q000096:biosynthesis / Q000235:genetics; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics*; D010641:Phenotype; D010920:Placenta / Q000098:blood supply* / Q000378:metabolism; D011225:Pre-Eclampsia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D011256:Pregnancy Outcome; D011270:Pregnancy, Animal; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D014327:Trophoblasts / Q000166:cytology / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C491089:GCM1 protein, human; C101631:Gcm1 protein, mouse; D009479:Neuropeptides; D009687:Nuclear Proteins; D014157:Transcription Factors; D004247:DNA