Abstract
Placental growth factor (PlGF), abundantly produced from trophoblasts is involved in placental angiogenesis. The regulatory mechanism of its expression is poorly understood. Hypoxia inducible factors (HIFs) are centrally involved in the modulation of cellular function in response to low oxygen conditions. This study aimed to clarify HIF1α and HIF2α expression patterns during cytotrophoblast differentiation into syncytiotrophoblast and the impact of any changes on PlGF expression. HIF proteins were induced remarkably under low oxygen condition (2%). HIF1α expression decreased and HIF2α expression increased when syncytialization of cultured cytotrophoblasts is progressed. Those expression changes of HIF proteins in the process of in-vitro syncytialization was congruent with the immunohistochemical findings in preeclamptic placenta as well as uncomplicated placenta. Low oxygen condition was also associated with reduced PlGF production in syncytializing primary cells and BeWo choriocarcinoma cells. Small interfering RNA-mediated HIF2α knockdown in BeWo cells abrogated hypoxia-associated decreases in PlGF secretion; HIF1α silencing had no significant effect on PlGF secretion. In summary, HIF2α, rather than HIF1α, is most affected by reduced oxygen level during syncytialization and increases in HIF2α trigger a reduction of PlGF production. Our findings suggest new and important connections between HIF proteins and PlGF pathways in the regulation of placental angiogenesis.
Highlights
Drastic alterations in local oxygen concentration accompany placental development
The acquisition of human chorionic gonadotropin (HCG) secretion capacity suggested that the stages of cell differentiation in our cultured trophoblast model corresponded to cytotrophoblasts during the period of 0 to 24 hours in culture and syncytiotrophoblast during the period of 72 to 96 hours in culture
We evaluated the protein and mRNA expression patterns of HIF1α and hypoxia inducible factors (HIFs) 2α in an in-vitro syncytialization model in which highly purified cytotrophoblasts are differentiated into syncytiotrophoblast over the course of 96 hours
Summary
Drastic alterations in local oxygen concentration accompany placental development. Oxygen concentrations in the inter-villous space at 8 weeks of gestation is estimated to be about 3 to 5%; this increases to about 8 to 10% after the completion of uterine spiral artery remodeling[1]. The transcription factors hypoxia inducible factors (HIFs) 1α and 2α are central to the process of adaptation to hypoxic conditions by controlling the expression of genes involved in diverse biological processes such as angiogenesis, vascular tone, glycolysis, mitochondrial function, cell growth and survival[7]. As their names indicate, HIF protein functions rely on the local oxygen concentrations. Uncontrolled enhancement of HIF proteins by VHL gene deletion causes deranged vasculogenesis in the murine placenta[13] These observations suggest HIF proteins are critical for trophoblast differentiation and the regulation of placental vascular formation. The molecular mechanisms to regulate those angiogenic molecules in trophoblast cells are not fully elucidated
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