HIF-2?, but not HIF-1?, mediates hypoxia-induced up-regulation of Flt-1 gene expression in placental trophoblasts.

ABSTRACT: Placental hypoxia and elevated levels of circulating soluble Fms-like tyrosine kinase-1 (sFlt-1), an anti-angiogenic factor, are closely related to the pathogenesis of preeclampsia. Although sFlt-1 secretion from the placental trophoblasts is increased under hypoxic conditions, the underlying molecular mechanism remains unclear. Previously, an authentic hypoxia response element in the Flt-1 gene promoter was shown to be a potential binding site for hypoxia-inducible factors (HIFs). Here, we investigated the roles of HIF-1? and HIF-2? in Flt-1 gene expression in trophoblast-derived choriocarcinoma cell lines and cytotrophoblasts exposed to hypoxic conditions. In the cell lines, increased expression of sFlt-1 splice variants and nuclear accumulation of HIF-1? and HIF-2? were observed after hypoxic stimulation. A specific small interfering RNA or an inhibitor molecule targeting HIF-2? decreased hypoxia-induced up-regulation of Flt-1 gene expression. Moreover, in cytotrophoblasts, increased sFlt-1 mRNA expression and elevated sFlt-1 production were induced by hypoxic stimulation. Notably, hypoxia-induced elevation of sFlt-1 secretion from the cytotrophoblasts was inhibited by silencing the HIF-2?, but not HIF-1? mRNA. These findings suggest that hypoxia-induced activation of HIF-2? is essential for the increased production of sFlt-1 proteins in trophoblasts. Targeting the HIF-2? may be a novel strategy for the treatment of preeclampsia.

SUBMITTER: Sasagawa T 

PROVIDER: S-EPMC6255857 | biostudies-other | 2018 Nov

REPOSITORIES: biostudies-other