sFlt-1-enriched exosomes induced endothelial cell dysfunction and a preeclampsia-like phenotype in mice.
sFlt-1-enriched exosomes induced endothelial cell dysfunction and a preeclampsia-like phenotype in mice.
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DOI：
10.1016/j.cyto.2023.156190
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发表时间：
2023-04
期刊：
影响因子：
3.8
通讯作者：
Xiaojie Huang;L. Jia;Yuanhui Jia;Xiang-Hong Xu;Ruixue Wang;Mengtian Wei;Han Li;Hao Peng;Yingying Wei;Qi-zhi He;K. Wang
中科院分区：
文献类型：
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作者：
Xiaojie Huang;L. Jia;Yuanhui Jia;Xiang-Hong Xu;Ruixue Wang;Mengtian Wei;Han Li;Hao Peng;Yingying Wei;Qi-zhi He;K. Wang
子痫前期(Preeclampsia，PE)是一种以母体内皮功能障碍和终末器官损害为特征的妊娠高血压疾病。我们先前的工作表明，PE患者来源的外切体含有较高水平的可溶性FMS样酪氨酸激酶-1(sFlt-1)，并显著诱导内皮功能障碍和PE的发生。然而，sFlt-1丰富的外切体(sflt-1-exo)在PE发育中的作用机制尚不清楚。在这里，我们发现滋养层细胞来源的sFlt-1-Exo处理显著抑制了人脐静脉内皮细胞(HUVEC)的迁移和管状形成，并增加了sFlt-1的分泌。从机制上讲，我们发现细胞培养上清液中sFlt-1的分泌增加归因于HUVECs中sFlt-1转录的增强。重要的是，我们观察到，用sFlt-1-Exo或重组小鼠sFlt-1治疗怀孕小鼠会引发类似子痫前期的表型，特征是血压升高、蛋白尿、血浆sFlt-1增加和不良妊娠结局。这些结果有力地表明，sFlt-1-Exo诱导的内皮功能障碍可能部分归因于内皮细胞中sFlt-1的上调，可能导致小鼠出现先兆子痫样表型。
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.