小剂量阿司匹林调节可溶性endoglin表达对子痫前期的预防作用及其机制

Preeclampsia is a severe complication of pregnancy threating maternal and fetal health. The pathogenesis of preeclampsia is complicated. We have demonstrated that over expression of serum soluble endoglin (sEng) derived from placenta is a key mechanism of preeclampsia pathogenesis. Metabolic syndrome is a risk factor of preeclampsia. Low dose aspirin (LDA) is partially effective to prevent preeclampsia in high-risk population. Peroxisome proliferator activated receptor-γ (PPAR-γ), which is closely related with metabolic syndrome, can leads to pregnant complications with its dysfunction. Our previous research have verified that PPAR-γ suppression leads to over expression of sEng in trophoblasts. In this study, low dose aspirin activates PPAR-γ, which blocks over expression of sEng in trophoblasts and further prevents preeclampsia in high risk population, are required to be confirmed. We plan to investigate the dose effect of aspirin also. By in-vitro trophoblast cell research, we intend to discover the relationship between LDA and PPAR-γ, sEng pathway, trophoblast invasion capacity among groups of different doses of aspirin and different PPAR-γ activation conditions. We also compare the response of trophoblaststo aspirin between high-risk population and low-risk population. We will establish a mouse model of preeclampsia via PPAR-γ antagonist, by which to verify the correlation between LDA and PPAR-γ, sEng pathway in target organs including placenta, serum and kidney, as well as the dose effect of LDA.

子痫前期是妊娠期特发的疾病，发病机制复杂。母体胎盘产生过多抗血管活性因子可溶性endoglin（sEng）与发病密切相关。代谢综合征是子痫前期的高危因素，小剂量阿司匹林（LDA）有预防作用，但限用于高危人群。过氧化物酶体增殖物激活受体γ（PPAR-γ）与代谢综合征密切相关，其功能异常也可导致妊娠相关疾病。前期研究证实PPAR-γ受抑制使绒毛滋养细胞表达sEng增加。本研究假设LDA预防高危人群子痫前期的机制为激活PPAR-γ抑制滋养细胞过表达sEng，并存在剂量效应。通过滋养细胞体外实验，探讨LDA与PPAR-γ和sEng 通路之间的关系，比较不同阿司匹林剂量和不同PPAR-γ激活状态下滋养细胞的侵袭能力，并比较高危与非高危人群早孕期滋养细胞对阿司匹林的反应。通过PPAR-γ拮抗剂建立子痫前期小鼠模型，从胎盘、外周血、肾脏三个靶器官验证LDA与PPAR-γ和sEng的关系，并探讨剂量效应。

子痫前期是严重影响母儿健康的妊娠期特发性疾病，发病机制复杂。母体胎盘产生过多抗血管活性因子可溶性endoglin（sEng）与发病密切相关。代谢综合征是子痫前期的高危因素，小剂量阿司匹林（LDA）有预防作用，但限用于高危人群。过氧化物酶体增殖物激活受体γ（PPAR-γ）与代谢综合征密切相关，其功能异常也可导致妊娠相关疾病。本研究内容为验证LDA预防高危人群子痫前期的机制为激活PPAR-γ抑制滋养细胞过表达sEng，并存在剂量效应。本研究通过人早孕期绒毛组织体外实验表明：高危人群绒毛组织PPAR-γ mRNA表达略低于低危人群，而sEng略高于低危人群，但无统计学差异；HTR-8/Svneo经LDA处理后PPAR-γmRNA表达有升高的趋势，但无统计学差异。通过PPAR-γ拮抗剂建立小鼠PE模型的实验结果表明，PPAR-γ拮抗剂可诱导小鼠出现PE表型，包括血压、尿蛋白的升高，抗血管活性因子sEng和促炎症因子IL-1β表达的增加，胎盘PPAR-γmRNA表达下降，胎盘和肾脏特征性的病理表现；预防性LDA可以避免或减轻PPAR-γ拮抗剂诱导的以上小鼠PE表型；LDA对PPAR-γ拮抗剂诱导PE模型鼠的预防作用存在一定的剂量效应。此结果对指导临床LDA预防子痫前期的应用和理解LDA的作用机制有重要意义。本研究对PE的各临床亚型进行了胎盘差异蛋白质组学研究，各组间共有98个显著差异蛋白，此结果证实了PE临床亚型分型的可行性，并为临床分型提供了分子学依据。