Department of Obstetrics and Gynecology, National Cheng Kung University Hospital.
Department of Cell Biology and Anatomy.
J Hypertens. 2019 Dec;37(12):2461-2469. doi: 10.1097/HJH.0000000000002185.
Recent studies suggested that prophylactic aspirin prior to 16 weeks of gestation in high-risk patients may reduce the risk of developing preeclampsia; however, the exact mechanism of aspirin's effect on the pathophysiology of preeclampsia is not clear. This study was designed to investigate the effect of aspirin on trophoblast cell function and its effect on soluble fms-like tyrosine kinase 1 (sFlt-1) production to elucidate the preventive mechanisms for preeclampsia.
We used two human trophoblastic cell lines (HTR-8/SVneo and JAR) and freshly isolated cytotrophoblasts from normal and preeclamptic placenta at term to determine the effect of aspirin on trophoblast cell function. Trophoblasts were pretreated with aspirin, and then cell functions and sFlt-1 expression were assessed. Our results showed that aspirin promoted trophoblast invasion not only in HTR-8/SVneo and JAR cells, but also in isolated cytotrophoblasts. sFlt-1 production was repressed by aspirin in a dose-dependent manner. By adding Flt-1 recombinant protein, the trophoblast invasion ability was inhibited in HTR-8/SVneo cells, which was reversed by Flt-1 small interfering ribonucleic acid knockdown. In addition, metalloproteinase 2/9 expression and activity were activated by aspirin but inhibited by sFlt-1. Aspirin also downregulated Akt phosphorylation, and trophoblast invasiveness was facilitated under Akt inhibitor treatment.
Aspirin enhances cell invasiveness and inhibits sFlt-1 production in trophoblasts. Moreover, sFlt-1 itself also inhibits trophoblast invasion. Our novel findings suggest that the preeclampsia prevention effect of aspirin may be exerted through these two mechanisms.
最近的研究表明，高危患者在妊娠 16 周前预防性服用阿司匹林可能降低子痫前期的发病风险；然而，阿司匹林对子痫前期病理生理学影响的确切机制尚不清楚。本研究旨在探讨阿司匹林对滋养细胞功能的影响及其对可溶性 fms 样酪氨酸激酶 1（sFlt-1）产生的影响，以阐明子痫前期的预防机制。
我们使用了两种人滋养细胞系（HTR-8/SVneo 和 JAR）和足月正常及子痫前期胎盘分离的滋养细胞，以确定阿司匹林对滋养细胞功能的影响。用阿司匹林预处理滋养细胞，然后评估细胞功能和 sFlt-1 表达。结果表明，阿司匹林不仅促进了 HTR-8/SVneo 和 JAR 细胞，而且促进了分离的滋养细胞的侵袭。阿司匹林呈剂量依赖性抑制 sFlt-1 的产生。在 HTR-8/SVneo 细胞中，加入 Flt-1 重组蛋白抑制滋养细胞的侵袭能力，而 Flt-1 小干扰 RNA 敲低可逆转这一作用。此外，阿司匹林激活基质金属蛋白酶 2/9 的表达和活性，但被 sFlt-1 抑制。阿司匹林还下调 Akt 磷酸化，在 Akt 抑制剂处理下促进滋养细胞侵袭。
阿司匹林增强滋养细胞的细胞侵袭能力并抑制 sFlt-1 的产生。此外，sFlt-1 本身也抑制滋养细胞的侵袭。我们的新发现表明，阿司匹林的子痫前期预防作用可能通过这两种机制发挥作用。
