Maternal endothelial dysfunction in preeclampsia is associated with increased soluble fms-like tyrosine kinase-1 (sFlt-1), a circulating antagonist of vascular endothelial growth factor and placental growth factor. Angiotensin II (Ang II) is a potent vasoconstrictor that increases concomitant with sFlt-1 during pregnancy. Therefore, we speculated that Ang II may promote the expression of sFlt-1 in pregnancy. Here we report that infusion of Ang II significantly increases circulating levels of sFlt-1 in pregnant mice, thereby demonstrating that Ang II is a regulator of sFlt-1 secretion in vivo. Furthermore, Ang II stimulated sFlt-1 production in a dose- and time-dependent manner from human villous explants and cultured trophoblasts but not from endothelial cells, suggesting that trophoblasts are the primary source of sFlt-1 during pregnancy. As expected, Ang II-induced sFlt-1 secretion resulted in the inhibition of endothelial cell migration and in vitro tube formation. In vitro and in vivo studies with losartan, small interfering RNA specific for calcineurin and FK506 demonstrated that Ang II-mediated sFlt-1 release was via Ang II type 1 receptor activation and calcineurin signaling, respectively. These findings reveal a previously unrecognized regulatory role for Ang II on sFlt-1 expression in murine and human pregnancy and suggest that elevated sFlt-1 levels in preeclampsia may be caused by a dysregulation of the local renin/angiotensin system.

中文翻译：

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血管紧张素II通过钙调神经磷酸酶信号传导途径诱导妊娠期可溶性fms样酪氨酸激酶-1释放。

先兆子痫的母体内皮功能障碍与可溶性fms样酪氨酸激酶1（sFlt-1）增加有关，后者是血管内皮生长因子和胎盘生长因子的循环拮抗剂。血管紧张素II（Ang II）是一种有效的血管收缩剂，在怀孕期间会增加sFlt-1。因此，我们推测Ang II可能在妊娠中促进sFlt-1的表达。在这里我们报告说，Ang II的输注显着增加了妊娠小鼠中sFlt-1的循环水平，从而表明Ang II是体内sFlt-1分泌的调节剂。此外，Ang II刺激人绒毛外植体和培养的滋养细胞以剂量和时间依赖性方式刺激sFlt-1的产生，但不是来自内皮细胞，这表明孕期滋养细胞是sFlt-1的主要来源。如预期的那样，Ang II诱导的sFlt-1分泌导致内皮细胞迁移的抑制和体外管的形成。用氯沙坦进行的体外和体内研究表明，钙调神经磷酸酶和FK506特异的小干扰RNA证明Ang II介导的sFlt-1释放分别是通过Ang II 1型受体激活和钙调神经磷酸酶信号传导实现的。这些发现揭示了Ang II对鼠和人妊娠中sFlt-1表达的调控作用尚未得到认识，并暗示先兆子痫中sFlt-1水平升高可能是由于局部肾素/血管紧张素系统失调引起的。钙调神经磷酸酶和FK506特异的小干扰RNA证明Ang II介导的sFlt-1释放分别是通过Ang II 1型受体激活和钙调神经磷酸酶信号传导实现的。这些发现揭示了Ang II对鼠和人妊娠中sFlt-1表达的调控作用尚未得到认识，并暗示先兆子痫中sFlt-1水平升高可能是由于局部肾素/血管紧张素系统失调引起的。钙调神经磷酸酶和FK506特异的小干扰RNA证明Ang II介导的sFlt-1释放分别是通过Ang II 1型受体激活和钙调神经磷酸酶信号传导来实现的。这些发现揭示了Ang II对鼠和人妊娠中sFlt-1表达的调控作用尚未得到认识，并暗示先兆子痫中sFlt-1水平升高可能是由于局部肾素/血管紧张素系统失调引起的。