HIF-3[alpha] affects preeclampsia development by regulating EVT growth via activation of the Flt-1/JAK/STAT signaling pathway in hypoxia

Preeclampsia (PE) is a common obstetric disease occurring after 20 weeks of gestation. Hypoxia-inducible factor (HIF)-3[alpha] potentially functions as a regulatory factor in PE development, however its specific molecular mechanism remains to be elucidated. The present study aimed to investigate the function of HIF-3[alpha] in trophoblast cell line HTR-8/SVneo, to provide a better understanding of the pathology and treatment of PE. Normal and PE placentas were obtained from pregnant women. HTR8/SVneo cells were cultured under the condition of normoxia or hypoxia, pretreated with or without AG490, then transfected with HIF-3[alpha]. The gene expression levels of HIF-3[alpha] and Fms like tyrosine kinase receptor (Flt) 1 extracted from the placentas and cells were detected by reverse transcription-quantitative PCR, and the expression levels of proteins and Janus kinase signal transducer and activator of transcription (JAK/STAT) phosphorylation were detected by western blot analysis. Viability and apoptosis of the treated cells were assessed by MTT and flow cytometry. The results demonstrated that HIF-3[alpha] and Flt-1 gene expression levels of PE placentas were reduced compared with normal placentas. Under a hypoxic environment, the expression levels of HIF-3[alpha] and Flt-1, the phosphorylation of JAK/STAT and the cell viability of HTR8/SVneo cells were increased at first and then reduced, whereas cell apoptosis was promoted over time. Under chronic hypoxia, the expression levels of HIF-3[alpha] and Flt-1, JAK/STAT pathway phosphorylation and cell viability of AG490-treated HTR8/SVneo cells were reduced, but cell apoptosis was promoted. However, the upregulation of HIF-3[alpha] in HTR8/SVneo cells markedly reversed the effects of AG490 on the cells under hypoxia. Thus, the present study preliminarily demonstrated that HIF-3[alpha] was involved in PE development by regulating extravillous cytotrophoblast growth via Flt-1 and the JAK/STAT signaling pathway. Key words: preeclampsia, extravillous cytotrophoblast, Fms-like tyrosine kinase receptor 1, hypoxia-inducible factor-3a, Janus kinase-signal transducer 2/signal transducer and activator of transcription 3 signaling pathway