Physiological Hypoxia Is Involved in Trophoblast Differentiation via HIF1α Mediating Upregulation of PLOD2

LI Cong^1,2, LIU Taihang², WANG Yongheng², DING Yubin^1,2, LI Zhuohang², WANG Yingxiong^2*

(¹School of Public Health and Management, Chongqing 400016, China; ²Joint International Research Laboratory of Reproductive and Development, Department of Reproductive Biology, Chongqing Medical University, Chongqing 400016, China)

Abstract:

Physiological hypoxia plays an important role in trophoblast cell differentiation during placental development. HIF1α is one of the key factors that respond to hypoxia, but it is not fully understood how physiological hypoxia modulates placental development through HIF1α. In this study, the downstream target genes of HIF1α and the genes that were differentially expressed during cytotrophoblast cells differentiation into extravillous trophoblast cells were first analyzed by using bioinformatics methods. The genes were considered as the potential target genes involved in hypoxia-induced EVT formation through HIF1α signaling. It was further found that under physiological hypoxic conditions (8% O2), HIF1α and its downstream target genes PLOD2, HPCAL1, SLC16A3, FAM174B, and SYDE1 were upregulated, while NREP and CD4 were downregulated. Interestingly, the expression pattern of these target genes was similarly observed when HIF1α was overexpressed in the cells. Knockdown of PLOD2 impaired cytoskeletal actin remodeling, which resulted in the inhibition of epithelial-mesenchymal transition, outgrowth, migration, and invasion of trophoblast cells. This study contributes to understanding how physiological hypoxia (8% O2) induces the upregulation of HIF1α, as well as how HIF1α promotes trophoblast migration and invasion via its downstream target genes such as PLOD2.