Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China; Clinical and Translational Research Center, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China.
Clinical and Translational Research Center, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China.
Cytokine. 2023 Jun;166:156190. doi: 10.1016/j.cyto.2023.156190. Epub 2023 Apr 14.
Preeclampsia (PE) is a hypertensive disorder of pregnancy characterized by maternal endothelial dysfunction and end-organ damage. Our previous work demonstrated that PE patient-derived exosomes contained higher levels of soluble FMS-like tyrosine kinase-1 (sFlt-1) and significantly induced endothelial dysfunction and PE development. However, the mechanisms underlying the effect of sFlt-1-enriched exosomes (sFlt-1-Exo) on PE development are poorly characterized. Here, we revealed that trophoblast-derived sFlt-1-Exo treatment induced significant inhibition of human umbilical vein endothelial cell (HUVEC) migration and tube formation, as well as an increase in sFlt-1 secretion. Mechanistically, we found that the increased sFlt-1 secretion in the cell culture medium was attributed to enhanced transcription of sFlt-1 in HUVECs. Importantly, we observed that treating pregnant mice with sFlt-1-Exo or recombinant mouse sFlt-1 triggered a preeclampsia-like phenotype, characterized by elevated blood pressure, proteinuria, increased plasma sFlt-1 and adverse pregnancy outcomes. These results strongly suggested that sFlt-1-Exo-induced endothelial dysfunction could be partially attributed to the upregulation of sFlt-1 in endothelial cells, potentially leading to the development of a preeclampsia-like phenotype in mice.
子痫前期（PE）是一种妊娠高血压疾病，其特征为母体血管内皮功能障碍和终末器官损伤。我们之前的研究表明，PE 患者来源的外泌体中含有更高水平的可溶性 FMS 样酪氨酸激酶-1（sFlt-1），并能显著诱导血管内皮功能障碍和 PE 发生。然而，sFlt-1 富集的外泌体（sFlt-1-Exo）对 PE 发生发展的作用机制尚未明确。在此，我们揭示了滋养层来源的 sFlt-1-Exo 处理能显著抑制人脐静脉内皮细胞（HUVEC）的迁移和管腔形成，并增加 sFlt-1 的分泌。在机制上，我们发现细胞培养液中 sFlt-1 分泌的增加归因于 HUVEC 中 sFlt-1 的转录增强。重要的是，我们观察到用 sFlt-1-Exo 或重组鼠 sFlt-1 处理妊娠小鼠会引发子痫前期样表型，表现为血压升高、蛋白尿、血浆 sFlt-1 增加和不良妊娠结局。这些结果强烈表明，sFlt-1-Exo 诱导的血管内皮功能障碍可能部分归因于内皮细胞中 sFlt-1 的上调，这可能导致小鼠发生子痫前期样表型。
