Transcriptionally active syncytial aggregates in the maternal circulation may contribute to circulating soluble fms-like tyrosine kinase 1 in preeclampsia.
Transcriptionally active syncytial aggregates in the maternal circulation may contribute to circulating soluble fms-like tyrosine kinase 1 in preeclampsia.
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DOI：
10.1161/hypertensionaha.111.182170
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发表时间：
2012-02
期刊：
影响因子：
--
通讯作者：
Karumanchi SA
中科院分区：
文献类型：
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作者：
Rajakumar A;Cerdeira AS;Rana S;Zsengeller Z;Edmunds L;Jeyabalan A;Hubel CA;Stillman IE;Parikh SM;Karumanchi SA
妊娠特异性疾病先兆子痫、新发高血压和蛋白尿的主要表现与胎盘产生的细胞外蛋白sFlt 1（可溶性fms样酪氨酸激酶1）有关，该蛋白损伤母体血管。然而，与基质高度结合的sFlt 1进入体循环的机制仍不清楚。在这里，我们报告说，先兆子痫胎盘的最外层，合体滋养层，形成丰富的“结”，富含sFlt 1蛋白。这些合胞体结很容易从合胞体滋养层分离，产生游离的多核聚集体（直径50-150 μm），这些聚集体负载sFlt 1蛋白和mRNA，具有代谢活性，能够进行从头基因转录和翻译。妊娠晚期母体血浆中至少25%的可测量sFlt 1与循环胎盘微粒结合。我们的结论是，从胎盘分离的合胞体结的结果在自由的，转录活性的合胞体聚集体，代表一个自主的来源sFlt 1交付到母体循环。合胞体结形成、合胞体聚集体脱落和母体循环中胎盘微粒的出现的过程似乎在先兆子痫中大大加速，并且可能导致以这种疾病为特征的母体血管损伤。
The cardinal manifestations of the pregnancy-specific disorder preeclampsia, new-onset hypertension and proteinuria that resolve with placental delivery, have been linked to an extracellular protein made by the placenta, sFlt1 (soluble fms-like tyrosine kinase 1), that injures the maternal vasculature. However, the mechanisms by which sFlt1, which is heavily matrix-bound, gains access to the systemic circulation remain unclear. Here we report that the preeclamptic placenta’s outermost layer, the syncytiotrophoblast, forms abundant “knots” that are enriched with sFlt1 protein. These syncytial knots easily detach from the syncytiotrophoblast, resulting in free, multinucleated aggregates (50–150 μm diameter) that are loaded with sFlt1 protein and mRNA, are metabolically active, and are capable of de novo gene transcription and translation. At least 25% of the measurable sFlt1 in 3rd trimester maternal plasma is bound to circulating placental microparticles. We conclude that detachment of syncytial knots from the placenta results in free, transcriptionally active syncytial aggregates that represent an autonomous source of sFlt1 delivery into the maternal circulation. The process of syncytial knot formation, shedding of syncytial aggregates, and appearance of placental microparticles in the maternal circulation appears to be greatly accelerated in preeclampsia and may contribute to the maternal vascular injury that characterizes this disorder.