Faculty of Health Sciences, University of Ottawa, Ottawa, Ontario, Canada.
Hypertension. 2012 Mar;59(3):732-9. doi: 10.1161/HYPERTENSIONAHA.111.183939. Epub 2012 Jan 23.
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.
子痫前期是一种危及生命的疾病，其特征为母体妊娠高血压和蛋白尿，这些是由胎盘功能障碍引起的。胎盘异常包括异常的合体滋养层和胎盘转录因子 Gcm1 表达减少 50%。在小鼠中，Gcm1 基因纯合缺失会阻止合体滋养层分化，并导致胚胎致死。我们使用杂合 Gcm1 突变体（Gcm1(+/-)）来检验以下假说：胎盘 Gcm1 的低功能表达导致合体滋养层分化缺陷，并引起类似于子痫前期的母体和胎盘表型。我们让野生型雌性小鼠与 Gcm1(+/-)雄性小鼠交配，以获得携带约 50% Gcm1(+/-)胚胎的野生型母亲。Gcm1(+/-)胎盘存在合体滋养层异常，包括 Gcm1 调节的 SynB 基因表达减少、sFlt1 表达升高、分隔母体和胎儿循环的两绒毛膜间膜增厚，以及在合体滋养层中存在坏死和母体-胎儿转运受损的电子显微镜证据。通过组织形态计量学和微计算机断层扫描成像来定量胎儿胎盘血管生成。在 Gcm1(+/-)中，它比野生型同窝仔鼠约大 30%，而胎盘血管内皮生长因子 A（Vegfa）表达和胎儿及胎盘重量没有差异。携带 Gcm1(+/-)胚胎的野生型母亲在妊娠晚期出现高血压（118±2 与对照组的 109.6±0.7mmHg 相比；P<0.05）。接下来，我们将胎儿胎盘血管生成与人类对照和病理性妊娠的胎盘 Gcm1 表达相关联，发现与小鼠一样，当 GCM1 蛋白表达减少时，胎儿胎盘血管生成增加（R(2)=-0.45；P<0.05）。这些结果支持胎盘 Gcm1 表达减少作为人类子痫前期合体滋养层分化缺陷和母体及胎盘表型的致病因素的作用。
