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.