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Contribution of placental 11β-HSD2 to the pathogenesis of preeclampsia
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  • Gang Wang,
  • Yan Huang,
  • Tianxiao Hu,
  • Baozhen Zhang,
  • Zhengshan Tang,
  • Ruojing Yao,
  • Ying Huang,
  • Xiujun Fan,
  • Xin Ni
Gang Wang
Second Military Medical University
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Yan Huang
Second Military Medical University
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Tianxiao Hu
Second Military Medical University
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Baozhen Zhang
Shenzhen Institutes of Advanced Technology
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Zhengshan Tang
Xiangya Hospital
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Ruojing Yao
Xiangya Hospital Central South University
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Ying Huang
Maternity and Child Health Hospital of Pudong New District
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Xiujun Fan
Shenzhen Institutes of Advanced Technology Chinese Academy of Sciences
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Xin Ni
Xiangya Hospital Central South University
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Abstract

Background and purposes Preeclampsia(PE) is associated with abnormal function of various factors in placentas. 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) is abundantly expressed in placenta and controls the local availability of glucocorticoids. We aimed to elucidate the role of 11β-HSD2 in the pathogenesis of PE. Experimental approach Pregnant rats were administrated with 11β-HSD2 inhibitor carbenoxolone (CBX) subcutaneously or by placenta-targeted delivery system. The blood pressure, renal and placental morphology, placental blood flow and circulatory levels of fms-like tyrosine kinase 1 (sFlt1) and placental growth factor (PlGF) were subsequently examined. Cultured human trophoblasts were used to investigate the role of 11β-HSD2 in migration and invasion function and sFlt1 release in vitro. Key results Subcutaneous administration and placenta-targeted delivery of CBX resulted in the hallmark of PE-like features including hypertension, proteinuria, renal damages, elevated circulatory sFlt1 level and increased sFlt1/ PlGF in pregnant rats. These animals displayed reduced trophoblast invasion in uterus, impaired spiral artery remodeling and reduced placental blood flow. In vitro study showed that 11β-HSD2 dysfunction inhibited migration and invasion of the extravillous trophoblasts and promoted sFlt1 release in syncytiotrophoblasts. Mechanically, sFlt1 release induced by 11β-HSD2 dysfunction is mediated by enhancement of a disintegrin and metalloprotease (ADAM)17 transcription in placenta.