Galectin-9/CD44介导的滋养细胞-蜕膜巨噬细胞异常对话诱导胎盘血管重塑不良致子痫前期的分子机制

滋养细胞侵袭力下降、子宫螺旋动脉重塑不良是子痫前期（PE）特征性病理改变与重要病因，但其确切机制不清。我们发现PE患者胎盘滋养细胞（TROs）与外周血分泌高水平Galectin-9（Gal-9），募集与活化蜕膜巨噬细胞（M¢），并以CD44依赖性诱导其促炎表型、抑制其产生IL-8与内皮细胞管腔形成；孕早/中期应用Gal-9诱导孕鼠PE样改变，伴胎盘发育不良与子宫局部M¢异常变化，提示Gal-9/CD44介导的TROs与蜕膜M¢互作异常诱导了胎盘血管重塑障碍，致PE发生。拟探讨PE患者Gal-9上调原因；解析其对蜕膜M¢募集与训导机制及其抑制M¢产生IL-8的潜在原因，并建立TROs、血管内皮细胞与蜕膜M¢共培养体系模拟体外血管重塑模型以及构建CD44在M¢敲除鼠与PE模型解析Gal-9/CD44信号对体外胎盘血管重塑、体内胎盘发育与妊娠结局的影响及其机制，为PE早期预测与防治提供新思路。

The decreased trophoblast invasiveness and repaired uterine spiral artery remodeling are characteristic pathological changes and important etiology of preeclampsia (PE), but the underlying mechanism is still uncertain. Our previous studies found that trophoblasts (TROs) and peripheral blood of PE patients secreted high levels of galectin-9 (Gal-9), which recruited and activated decidual macrophages (M¢). Gal-9 induced the decidual M¢ into a proinflammatory phenotype, and inhibited their IL-8 production and endothelial cell lumen formation in a CD44-dependent manner. Exogenous Gal-9 treatment during the first/second trimester of pregnancy induced preeclampsia-like changes, accompanied with placental dysplasia and abnormal uterine M¢ alternations, indicating that aberrant interaction between TROs and decidual M¢ mediated by Gal-9/CD44 induced placental vascular remodeling disorder and finally resulted in preeclampsia. In this study, we will investigate the causes of Gal-9 up-regulation in PE patients, and analyze the mechanism of its effects on decidual M¢ recruitment and education, as well as the potential reasons for its suppression on IL-8 production by decidual M¢. We will establish the co-culture system of TROs, vascular endothelial cells and decidual M¢ to simulate the vascular remodeling model in vitro, and constructed mice model of conditioned-knockout of CD44 on macrophages and PE mice model to investigate the effect and mechanism of Gal-9/CD44 signal on in-vitro placental vascular remodeling, in-vivo placental development and pregnancy outcomes, providing new ideas for early prediction and prevention of PE.