人胎盘细胞滋养细胞（CTB）合体化形成的合体滋养细胞（STB）负责母胎间物质转运且具有重要的激素分泌功能。滋养细胞合体化异常可释放不良因子至母体并造成后者血管损伤，这与子痫前期的发生关系密切。基于前期结果，本研究提出PE发生的潜在新机理—“缺氧诱导滋养细胞合体化异常的表观遗传学机制”。研究利用细胞、胎盘/绒毛移植物等模型和横断面样本拟阐明：滋养细胞合体化过程受到DNA甲基转移酶（DNMTs）下调的被动去甲基化过程和 cAMP/PKA /CREB 信号通路激活的协同调控。缺氧环境可通过 HIF-1α 和/或 cAMP/PKA /CREB 信号通路干扰合体化过程中的 DNMTs 平衡,引起 ERVWE1(syn-1)等合体化相关基因启动子超甲基化/表达抑制,导致滋养细胞合体化障碍,并释放胎盘源性不良因子致血管内皮损伤和PE的发生。研究可能为PE的早期诊断和潜在的治疗方案提出新见解。

Human placental multinucleate syncytiotrophoblast (STB) is responsible for transport functions between maternal and fetal blood supplies and is a major site of protein synthesis and steroid production. Aberrant syncytialization causes the release of adverse factors and maternal vascular damage, and it is closely associated with progression of preeclampsia (PE). We hypothesize that hypoxia exposure inducing abnormal epigenetical changes in STB fusion might one of the underlying mechanisms of preeclampsia. Cell model and cross sectional study are used to clarify the following issues. STB syncytialization is under coordinated regulation of DNA methyltransferases (DNMTs) - induced demethylation and forskolin-activated cAMP/PKA/CREB signal pathway. Increased DNMTs expression induced by hypoxia through HIF-1α, coordinating with cAMP/PKA/CREB signal pathway， may increase promoter hypermethylation of syncytialization relative genes such as ERVWE1. Insufficient fusion may release placenta-derived reverse factors such as sFlt、sEng and causes vascular endothelial injury. The correlation between aberrant DNA methylation during STB syncytialization and preeclampsia development and occurrence. Our study will provide novel views on pathogenetic mechanism of preeclampsia, potential early diagnosis indicators and new intervention targets.