晚期氧化蛋白产物蓄积对胎盘血管形成的影响及机制研究

Placental vascular dysfunction can induced a series of placental associated complication. Defect of trophoblast invasion or disturbance of the pro-angiogenic/anti-angiogenic factors play an important role in the placental angiogenesis. Advanced oxidative protein products (AOPP) is an oxidant with high-bioactivity and has a wide-range pathologic effects.High level of AOPP was observed in patients with obesity, diabetes and metabolic symdrome, who were at high risk of developing placental associated complications when they were in pregnancy.In our previous work, higher levels of AOPP in plasma and placenta were observed in patients with preeclampsia. Moreover, it could enhances sflt-1 expression in trophoblasts. We speculate that AOPP might be a new pathologic sustances which can induce dysfunctions and in trophoblast cells. In the present study, we observed whether chronic AOPP accumulations could cause higher levels of adverse pregnancy outcomes in pregnant rats and the impact of AOPP on the placental vascular morphology and biologic functions. In the mean time, we stimulated HTR-8 'trophoblasts cell line with various concentrations of AOPP and observed its impacts on trophoblasts' invasiveness and anti-angiogenesis factor production.We also investigated the AOPP signal pathway on receptor and celluar dysfunction in trophoblasts so that we could demonstrate the possible effects of accumulation of AOPP on the angiogenesis in placenta.

胎盘血管形成异常可导致一系列胎盘源性疾病的发生。滋养细胞侵袭功能异常和胎盘局部促血管/抗血管生成因子比例失衡是影响胎盘血管形成的重要因素。晚期氧化蛋白产物（AOPP）是一种具有高度生物活性的代谢产物，在肥胖、糖尿病、代谢综合征等患者中广泛存在，上述人群又是胎盘源性疾病高危群体。我们前期研究表明，AOPP在子痫前期患者胎盘、血浆表达升高，并可诱导sFlt-1产生，与患者病情严重程度密切相关。推测 AOPP 可能是引起胎盘血管形成异常和诱导胎盘源性疾病发生新的致病物质。在本项研究，我们通过动物实验，观察慢性AOPP 蓄积对妊娠大鼠不良围产结局的发生及其对胎盘血管形成的影响。同时我们用不同浓度AOPP 刺激HTR-8滋养细胞，观察其侵袭功能变化和抗血管因子产生，探讨 AOPP诱导滋养细胞功能障碍和抗血管因子过度产生可能的受体途径及信号通路，以期阐明AOPP蓄积对胎盘血管形成和胎盘源疾病的影响。

胎盘血管形成异常可导致一系列胎盘源性疾病的发生。滋养细胞侵袭功能异常和胎盘局部促血管/抗血管生成因子比例失衡是影响胎盘血管形成的重要因素。晚期氧化蛋白产物（AOPP）是一种具有高度生物活性的代谢产物，在肥胖、糖尿病、代谢综合征等患者中广泛存在，上述人群又是胎盘源性疾病高危群体。我们前期研究表明，AOPP在子痫前期患者胎盘、血浆表达升高，并可诱导sFlt-1产生，与患者病情严重程度密切相关。推测 AOPP 可能是引起胎盘血管形成异常和诱导胎盘源性疾病发生新的致病物质。.在本项研究，我们利用离体滋养细胞与不同浓度AOPP共培养，结果提示：AOPP不但可降低滋养细胞对母体血管侵袭功能、诱导滋养细胞过度凋亡，并且可显著降低胎盘滋养细胞激素分泌。血栓素(Thrombin)是AOPP的下游产物。也是胎盘形成微血栓、增加胎盘缺血、缺氧及功能障碍的重要因素。为了阐明AOPP诱导胎盘血管生长因子产生失衡的潜在信号通路和致病机制主要通过Thrombin发挥作用，我们利用离体滋养细胞与不同浓度Thrombin共培养，同时利用siRNA技术敲除其中关键受体，我们发现AOPP-Thrombin引起胎盘血管生长因子产生失衡可能机制：AOPP蓄积 → AGE受体激活 → ROS过度产生 → Thrombin↑ →PAR-1活化/NADPH oxidase→ ROS过度产生 → sFlt-1↑。.上述研究提示：AOPP不仅参与子痫前期血管内皮功能障碍等病理环节，AOPP蓄积可能是引起孕早期胎盘发育异常的上游重要病理因素。