胎盘血管重铸障碍是子痫前期(PE)发病关键点。绒毛外滋养细胞(EVT)通过表达CXCL12调控NK细胞向蜕膜趋化，并驯化成蜕膜NK(dNK)细胞，在血管重铸中发挥始动作用。研究发现FoxO3与Bnip3介导的线粒体自噬有关，课题组前期在PE中证实FoxO3、Bnip3表达降低，Bnip3介导的线粒体自噬明显下降，EVT分泌CXCL12不足，dNK细胞减少。我们推测：EVT中转录因子FoxO3表达下调，使Bnip3介导的线粒体自噬异常，进而加重氧化应激损伤，造成EVT自身功能障碍，趋化因子 CXCL12表达减少，NK细胞向蜕膜归巢异常、dNK细胞驯化不良，打破母胎免疫稳态，发生胎盘浅着床和血管重铸障碍，导致PE。项目拟在细胞、组织及小鼠模型水平上应用分子生物学、亚细胞器蛋白质组学及基因工程等方法，从“细胞-胎盘组织-整体”全面验证该假说，将为深入研究PE的发病机制提供新思路。

Defective vascular remodeling in placenta is the key factor to the pathogenesis of preeclampsia (PE). Extravillous trophoblast cells (EVT) play an essential role at the onset of vascular remodeling by expressing CXCL12, which can exhibit chemotactic activity on natural killer cells (NK cells). Subsequently, NK cells are attracted to uterine decidua and become decidua nature kill cells (dNK cells). Researchers have identified that FoxO3 is associated with Bnip3-mediated-mitophagy. Meanwhile, our previous study has indicated that the expressions of FoxO3 and Bnip3 are downregulated, mitochondrial autophagy induced by Bnip3 is reduced significantly, CXCL12 secreted by EVT is compromised, and dNK cell population is declined in PE disease. Therefore, We hypothesize that the downregulation of transcription factor FoxO3 can induce the dysfunction of Bnip3-mediated-mitophagy in EVT leading to oxidative damage. As a consequence, chemotactic factor CXCL12 secreted by EVT is disrupted, which in term downregulate chemotactic activity in NK cells. These result in the impairment of immune homeostasis of the maternal-fetal interface, disruption of the placental superficial nidation, and defected vascular remodeling, which leads to the commencement of PE. To provide new insight into the pathogenesis of PE, we will apply numerous approaches such as molecular biology, subcellular proteomics, and genetic engineering on cell-tissue-animal models to further verify our hypothesis.