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.
Faculty of Health Sciences, University of Ottawa, Ottawa, Ontario, Canada. shannon.bainbridge [at] uottawa.ca
Hypertension. 2012 Mar;59(3):732-9
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