Abstract：
The placenta experiences a low-oxygen stage during early pregnancy. Aspirin is an effective preventative treatment for preeclampsia if applied early in pregnancy. Elevation of fibronectin (FN) level has been reported to be associated with preeclampsia; however, the role of FN in the physiological hypoxic phase and whether aspirin exerts its effect on FN at this hypoxic stage remain unknown. We determined pregnancy outcomes by injecting saline or recombinant FN protein into C57BL/6 pregnant mice and one group of FN-injected mice was fed aspirin. The effects of FN, the underlying pathways on trophoblast biology, and cilia formation under hypoxia were investigated in FN-pretreated or FN-knockdown HTR-8/SVneo cells in a hypoxic chamber (0.1 % O2). Preeclampsia-like phenotypes, including blood pressure elevation and proteinuria, developed in FN-injected pregnant mice. The fetal weight of FN-injected mice was significantly lower than that of non-FN-injected mice (p < 0.005). Trophoblast FN expression was upregulated under hypoxia, which could be suppressed by aspirin treatment. FN inhibited trophoblast invasion and migration under hypoxia, and this inhibitory effect occurred through downregulating ZEB1/2, MMP 9 and the Akt and MAPK signaling pathways. Ciliogenesis of trophoblasts was stimulated under hypoxia but was inhibited by FN treatment. Aspirin was shown to reverse the FN-mediated inhibitory effect on trophoblast invasion/migration and ciliogenesis. In conclusion, FN overexpression induces preeclampsia-like symptoms and impairs fetal growth in mice. Aspirin may exert its suppressive effect on FN upregulation and FN-mediated cell function in the hypoxic stage of pregnancy and therefore provides a preventative effect on preeclampsia development.
摘要：
胎盘在妊娠早期经历低氧阶段。如果在妊娠早期应用阿司匹林是先兆子痫的有效预防性治疗。据报道，纤连蛋白（FN）水平升高与先兆子痫有关；然而，FN在生理缺氧阶段的作用以及阿司匹林在该缺氧阶段是否对FN产生影响尚不清楚。我们通过向C57BL/6妊娠小鼠注射生理盐水或重组FN蛋白来确定妊娠结局，并一组注射FN的小鼠喂食阿司匹林。FN的影响，滋养细胞生物学的潜在途径，在缺氧室（0.1％O2）中，在FN预处理或FN敲低的HTR-8/SVneo细胞中研究了缺氧下纤毛的形成。子痫前期样表型,包括血压升高和蛋白尿,在注射FN的怀孕小鼠中发展。注射FN的小鼠的胎儿体重显著低于未注射FN的小鼠(p<0.005)。缺氧条件下滋养细胞FN表达上调,可以通过阿司匹林治疗来抑制。FN抑制缺氧条件下滋养细胞的侵袭和迁移,这种抑制作用是通过下调ZEB1/2、MMP9以及Akt和MAPK信号通路发生的。滋养细胞的纤毛生成在缺氧下受到刺激，但被FN处理抑制。阿司匹林被证明可以逆转FN介导的对滋养细胞侵袭/迁移和纤毛生成的抑制作用。总之,FN过表达诱导先兆子痫样症状并损害小鼠胎儿生长。阿司匹林可能在妊娠的缺氧阶段对FN上调和FN介导的细胞功能发挥抑制作用，因此对先兆子痫的发展具有预防作用。
