Department of Obstetrics and Gynecology, School of Medicine, Gyeongsang National University, JinJu, Republic of Korea.
Placenta. 2010 Jul;31(7):621-9. doi: 10.1016/j.placenta.2010.04.009. Epub 2010 May 21.
Although elevated expression of soluble fms-like tyrosine kinase 1 (sFlt1) plays a major role in the pathogenesis of pre-eclampsia, it is unclear how hypoxia regulates placental sFlt1 expression. Thus, we investigated sFlt1 expression in placentas from normal and preeclamptic pregnancies and in human placental hypoxia models in vitro to examine the role of the PI3K-Akt pathway in regulating the expression of this molecule.
We examined the expression of VEGF, PlGF, sFlt1, PI3K, Akt, and HIF-1 in placental samples from ten women with pre-eclampsia and ten normotensive control patients and in human choriocarcinoma trophoblast cells treated with 600muM CoCl(2) by Western blotting. Using models of placental hypoxia, we also determined whether inhibition of the PI3K-Akt pathway plays a direct role in regulating the expression of sFlt1.
The VEGF, PlGF, sFlt1, PI3K, Akt, and HIF-1 levels were significantly higher in the preeclamptic placentas than the normal placentas. In the placental hypoxia models, the expression of VEGF and PlGF increased in a time-dependent manner, whereas the expression of sFlt1 plateaued after 3h of CoCl(2) treatment. The expression levels of p-Akt and PI3K were maximal after 6 and 12h of CoCl(2) treatment, respectively. The expression of HIF-1alpha increased in a time-dependent manner with CoCl(2) treatment. Inhibition of the PI3K-Akt pathway with the PI3K-specific inhibitor LY294002 leads to decreased sFlt1 levels and unchanged or increased VEGF and PlGF levels.
Inhibition of the PI3K-Akt pathway may be a useful therapeutic approach, if it were to decrease sFlt1 secretion without inhibiting VEGF or PlGF secretion. This pathway provides a potential target for a new treatment strategy in patients with pre-eclampsia.
尽管可溶性 fms 样酪氨酸激酶 1（sFlt1）的高表达在子痫前期的发病机制中起着重要作用，但尚不清楚低氧如何调节胎盘 sFlt1 的表达。因此，我们研究了正常和子痫前期胎盘以及体外人胎盘低氧模型中 sFlt1 的表达，以探讨 PI3K-Akt 通路在调节这种分子表达中的作用。
我们通过 Western blot 检测了 10 例子痫前期患者和 10 例正常血压对照组患者胎盘组织中 VEGF、PlGF、sFlt1、PI3K、Akt 和 HIF-1 的表达，以及用 600μM CoCl2 处理的人绒毛膜癌细胞。通过胎盘缺氧模型，我们还确定了 PI3K-Akt 通路的抑制是否直接调节 sFlt1 的表达。
子痫前期胎盘组织中 VEGF、PlGF、sFlt1、PI3K、Akt 和 HIF-1 的水平明显高于正常胎盘。在胎盘缺氧模型中，VEGF 和 PlGF 的表达随时间呈依赖性增加，而 sFlt1 的表达在 CoCl2 处理 3 小时后达到平台期。p-Akt 和 PI3K 的表达水平分别在 CoCl2 处理 6 和 12 小时时达到最大值。HIF-1α的表达随 CoCl2 处理呈时间依赖性增加。PI3K 特异性抑制剂 LY294002 抑制 PI3K-Akt 通路可导致 sFlt1 水平降低，而 VEGF 和 PlGF 水平不变或升高。
如果抑制 PI3K-Akt 通路能降低 sFlt1 的分泌而不抑制 VEGF 或 PlGF 的分泌，那么该通路可能成为子痫前期患者新的治疗策略的潜在靶点。
