Hypoxia-inducible factor-1β is essential for upregulation of the hypoxia-induced FLT1 gene in placental trophoblasts.

Abstract

Placental hypoxia and increased levels of maternal blood anti-angiogenic protein, soluble fms-like tyrosine kinase-1 (sFLT1), are associated with the pathogenesis of pre-eclampsia. We have demonstrated that hypoxia-inducible factor (HIF)-2α mediates the upregulation of the hypoxia-induced FLT1 gene in trophoblasts and their cell lines. Here, we investigated the involvement of HIF-1β, which acts as a dimerization partner for HIF-α, in the upregulation of the FLT1 gene via hypoxia. We confirmed the interactions between HIF-1β and HIF-2α in the nuclei of BeWo, JAR and JEG-3 cells under hypoxia via co-immunoprecipitation. We found that hypoxia-induced upregulation of the FLT1 gene in BeWo cells and secretion of sFLT1 in human primary trophoblasts were significantly reduced by siRNAs targeting HIF-1β. Moreover, the upregulation of the FLT1 gene in BeWo cells induced by dimethyloxaloylglycine (DMOG) was also inhibited by silencing either HIF-2α or HIF-1β mRNA. It was recently shown that DNA demethylation increases both basal and hypoxia-induced expression levels of the FLT1 gene in three trophoblast-derived cell lines. In the demethylated BeWo cells, siRNAs targeting HIF-2α and HIF-1β suppressed the further increase in the expression levels of the FLT1 gene due to hypoxia or treatment with DMOG. However, luciferase reporter assays and bisulfite sequencing revealed that a hypoxia response element (-966 to -962) of the FLT1 gene is not involved in hypoxia or DMOG-induced upregulation of the FLT1 gene. These findings suggest that HIF-1β is essential for the elevated production of sFLT1 in the hypoxic trophoblasts and that the HIF-2α/HIF-1β complex may be a crucial therapeutic target for pre-eclampsia.

• Authors: Tadashi Sasagawa, Takeshi Nagamatsu, Manami Yanagisawa, Tomoyuki Fujii, Masabumi Shibuya
• Journal: Molecular human reproduction (Mol Hum Reprod) Vol. 27 Issue 12 (11 27 2021) ISSN: 1460-2407 [Electronic] England
• PMID: 34665260 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.

Chemical References

• ARNT protein, human
• Amino Acids, Dicarboxylic
• Aryl Hydrocarbon Receptor Nuclear Translocator
• FLT1 protein, human
• Vascular Endothelial Growth Factor Receptor-1
• oxalylglycine

Topics

• Amino Acids, Dicarboxylic (pharmacology)
• Aryl Hydrocarbon Receptor Nuclear Translocator (genetics, metabolism)
• Cell Hypoxia
• Cell Line, Tumor
• DNA Methylation
• Female
• Gene Expression Regulation, Developmental
• Humans
• Pregnancy
• Trophoblasts (drug effects, metabolism)
• Up-Regulation
• Vascular Endothelial Growth Factor Receptor-1 (genetics, metabolism)