Huang Shengbo, Zhang Yuanjin, Guo Yuanqing, Zhang Yi, Huang Junze, Yang Yujia, Qi Qifan, Zhao Luping, Xu Xin, Shen Yifei, Liang Chenmeizi, Yao Bingyi, Wang Xin
Changning Maternity and Infant Health Hospital and School of Life Sciences, Shanghai Key Laboratory of Regulatory Biology, East China Normal University.
Hypertension. 2025 Jul 16. doi: 10.1161/HYPERTENSIONAHA.125.25342.
Preeclampsia is a life-threatening pregnancy disorder characterized by hypertension and multiorgan dysfunction, posing significant risks to both maternal and fetal health. Although low-dose aspirin is widely recommended for preventing preeclampsia, the underlying mechanisms of action are still poorly understood, which hinders the optimization of therapeutic strategies.
We developed an in vitro hypoxia-induced preeclampsia model using human trophoblast organoids to replicate key pathological features. RNA sequencing identified dysregulated pathways and molecular targets. Functional assays assessed the effects of aspirin on trophoblast proliferation, mitochondrial activity, and hormonal regulation, focusing on the PI3K-AKT pathway and CYP (cytochrome P450) enzymes. We also analyzed the effects of aspirin in the N'-nitro-L-arginine-methyl ester hydrochloride rat models.
The hypoxia-induced preeclampsia model successfully mimicked clinical hallmarks, including elevated sFLT-1 (soluble fms-like tyrosine kinase 1)/PlGF (placental growth factor) ratios and oxidative damage. RNA sequencing revealed significant suppression of the PI3K-AKT-mTOR pathway and dysregulation of CYP enzymes. Aspirin treatment restored the sFLT-1/PlGF balance, reactivated the PI3K-AKT-mTOR pathway, and improved mitochondrial function, enhancing trophoblast proliferation. Furthermore, aspirin regulated CYP expression by increasing CYP19A1 and inhibiting CYP1A1, thereby improving placental hormonal homeostasis.
This study clarifies aspirin's multitarget mechanisms in alleviating preeclampsia, which include restoring the sFLT-1/PlGF balance, activating the PI3K-AKT-mTOR signaling pathway, optimizing mitochondrial function, and regulating CYP-mediated hormonal metabolism. These findings provide a mechanistic basis for aspirin's clinical effectiveness in preventing preeclampsia.
子痫前期是一种危及生命的妊娠疾病，其特征为高血压和多器官功能障碍，对母婴健康构成重大风险。尽管低剂量阿司匹林被广泛推荐用于预防子痫前期，但其潜在作用机制仍知之甚少，这阻碍了治疗策略的优化。
我们利用人滋养层类器官建立了一种体外缺氧诱导的子痫前期模型，以复制关键病理特征。RNA测序确定了失调的信号通路和分子靶点。功能试验评估了阿司匹林对滋养层细胞增殖、线粒体活性和激素调节的影响，重点关注PI3K-AKT信号通路和细胞色素P450（CYP）酶。我们还分析了阿司匹林在N'-硝基-L-精氨酸甲酯盐酸盐大鼠模型中的作用。
缺氧诱导的子痫前期模型成功模拟了临床特征，包括可溶性fms样酪氨酸激酶1（sFLT-1）/胎盘生长因子（PlGF）比值升高和氧化损伤。RNA测序显示PI3K-AKT-mTOR信号通路受到显著抑制，CYP酶失调。阿司匹林治疗恢复了sFLT-1/PlGF平衡，重新激活了PI3K-AKT-mTOR信号通路，改善了线粒体功能，增强了滋养层细胞增殖。此外，阿司匹林通过增加CYP19A1表达和抑制CYP1A1来调节CYP表达，从而改善胎盘激素稳态。
本研究阐明了阿司匹林在缓解子痫前期中的多靶点作用机制，包括恢复sFLT-1/PlGF平衡、激活PI3K-AKT-mTOR信号通路、优化线粒体功能以及调节CYP介导的激素代谢。这些发现为阿司匹林预防子痫前期的临床有效性提供了机制基础。
