儿茶酚胺氧位甲基转移酶/二甲氧基雌二醇在子痫前期发生中的作用机制

2-methoxyoestradiol (2-ME) is a natural metabolite of estradiol, which is generated by catechol-O-methyltransferase (COMT) in the placenta. It was reported that 2-ME has an important role in regulating vascular angiogenesis and endothelial cell biological behavior. Recently, an ex vivo study using COMT-deficient pregnant mice suggested that placental COMT deficiency induced preeclampsia（PE）-like phenotype resulting from an absence of 2-ME. In addition, 2-ME ameliorated all PE-like features without toxicity, indicating a relationship between COMT/2-ME and the onset of PE. In the previous study, we found that maternal serum 2-ME levels were elevated with the progression of pregnancy, however, maternal serum 2-ME levels were significantly decreased in patients diagnosed with PE. In this study, we will compare the differential expression of COMT/2-ME and related metabolites in PE based on the previous research. We will further discuss the effects and molecular mechanisms of 2-ME and related metabolites on placental angiogenesis and trophoblast biological behavior, providing the theoretical foundation of the pathogenesis of PE. Meanwhile, we will evaluate the value and significance of 2-ME and related metabolites on the diagnosis of PE, trying to find a new diagnostic marker or therapeutic target for PE.

二甲氧基雌二醇（2-ME）是雌激素代谢过程中由儿茶酚胺氧位甲基转移酶（COMT）催化生成的自然代谢产物， 参与调节血管生成及内皮细胞生物学行为。研究发现COMT基因敲除小鼠在妊娠晚期出现类似子痫前期（PE）的表型，且该表型可通过添加2-ME得到显著缓解，提示COMT/2-ME与PE发病密切相关。课题组前期已发现母体血清中2-ME水平随着孕周的增加而逐渐升高，但在PE患者血清中2-ME水平明显减低。课题拟在前期工作的基础上进一步分别比较COMT/2-ME及相关代谢物在PE中的差异性表达，深入探讨2-ME及其它小分子代谢物对胎盘血管生成和滋养层细胞生物学行为的影响及相关的分子机制，为深入探寻PE的发病机制提供理论依据；同时评估2-ME及其它特异性小分子代谢物作为PE临床诊断指标的价值及意义，为PE的早期诊断及干预提供新的靶点。

2-甲氧基雌二醇（2-ME）是17β-雌二醇的天然代谢产物，由儿茶酚胺氧位甲基转移酶（COMT）合成，参与调节血管生成及内皮细胞生物学行为。研究发现COMT基因敲除小鼠在妊娠晚期出现类似子痫前期(PE)的表型,且该表型可通过添加2-ME得到显著缓解,提示COMT/2-ME与PE发病密切相关。本研究发现随着妊娠的进展，母体2-ME浓度升高与正常足月妊娠相比，被诊断为轻度先兆子痫（mPE; 23％）和重度先兆子痫（sPE; 32％）的孕妇2-ME水平较低。同时，早产对照组的2-ME水平低于足月对照。胎盘中可溶性COMT（S-COMT）水平在孕晚期比孕早期增加了2.5倍，但胎盘中的膜结合COMT（MB-COMT）没有改变。2-ME抑制正常内皮细胞的增殖和迁移功能，且随着2-ME浓度的增高，抑制效果越明显。2-ME在20％O2下抑制胎盘滋养层细胞的增殖，但是2.5％O2下没有差异；2-ME在体外2.5％下促进胎盘滋养层细胞的迁移，20％O2下没有差异。考虑到2.5％O2是一种更接近体内的状态，这些数据表明2-ME水平的降低可能抑制滋养层细胞迁移，可能导致PE。