子痫前期发生机制不详，胎盘血管生成因子失衡能解释 “二阶段疾病模型”假说中第二阶段这些因子导致广泛内皮损伤，引起子痫前期症状，但不能解释第一阶段如何引起胎盘血管重铸障碍和缺氧，且这些因子的调控机制尚待研究。雌激素相关受体γ （ERRγ）是氧敏感性转录因子。我们的前期研究发现ERRγ能调控人滋养细胞中电压门控钾通道等基因，影响胎盘滋养细胞的分化和功能；ERRγ调控异常与子痫前期密切相关；ERRγ缺陷小鼠胎盘血管增生，VEGF等胎盘血管生成因子失衡。由此我们推测ERRγ通过调控胎盘血管生成因子影响胎盘血管重铸和血管内皮功能，引起子痫前期的发生。本项目通过滋养细胞体系、注射ERRγ激动剂孕鼠模型和人子痫前期病例，研究ERRγ对胎盘血管重铸的影响，明确其调控血管生成因子的分子机制，分析其作用时间和对早发型或迟发型子痫前期的不同作用机制。研究结果将为评估和治疗子痫前期提供崭新思路和途径。

The pathogenesis of preeclampsia remains unclear. The imbalance between placental anti-angiogenic factors and pro-angiogenic factors can explain the dysfunction of endothelial cells leading to preeclampsia on the second stage of “two-stage model of disease”, but can’t explain the failed remodeling of the maternal vessels on the first stage. And the regulation of these anti-angiogenic factors and pro-angiogenic factors is unclear. Estrogen-related receptor γ (ERRγ) is an oxygen dependent transcription factor. Our previous studies found that ERRγ affected the differentiation and function of human trophoblasts via control of a number of hypertension-associated genes including the voltage-gated potassium channels. ERRγ was associated with preeclampsia. Further, placentas of ERRγ-deficient mice manifested imbalance between placental anti-angiogenic factors and pro-angiogenic factors, compared to wild type mice. So we hypothesize that the aberrant regulation of ERRγ on placental angiogenic factors may play an important role in the pathogenesis of preeclampsia. In this project, we are going to investigate the effect of ERRγ on the remodeling of the maternal vessels of placenta and the regulation of ERRγ on placental angiogenic factors. We are also planning to analyze the blood pressure, protein urine, placental angiogenesis and expression of placental angiogenic factors from wild type pregnant mice injected with ERRγ agonist DY131 or vehicle, which may determine the critical working period of ERRγ. Meanwhile, we are going to determine the relationship of placental ERRγ expression with early-onset preeclampsia. The conclusions of this project may explain the different pathogenesis of early-onset or late-onset preeclampsia and provide a new way for evaluation and treatment of preeclampsia.