Increased expression of sFlt-1 in in vivo and in vitro models of human placental hypoxia is mediated by HIF-1
Increased expression of sFlt-1 in in vivo and in vitro models of human placental hypoxia is mediated by HIF-1
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DOI：
10.1152/ajpregu.00794.2005
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发表时间：
2006-10-01
影响因子：
2.8
通讯作者：
Caniggia, Isabella
中科院分区：
文献类型：
--
作者：
Nevo, Ori;Soleymanlou, Nima;Caniggia, Isabella
可溶性血管内皮生长因子受体-1（sFlt-1）在先兆子痫中的高表达在这种严重的人类妊娠疾病的发病机制中起着重要作用。尽管胎盘氧合减少被认为参与先兆子痫的发病机制，但尚不清楚氧如何调节胎盘sFlt-1表达。本文的目的是研究sFlt-1在人胎盘缺氧的体内和体外生理和病理模型中的表达，并了解缺氧诱导因子-1（HIF-1）在调节该分子表达中的作用。sFlt-1在胎盘绒毛中的表达在早期妊娠和高海拔胎盘的生理低氧条件下显著增加，以及在病理低氧条件下，如先兆子痫。在高海拔地区和先兆子痫组织中，sFlt-1定位于绒毛血管周围区域、合体滋养层和合体结内。在孕早期绒毛组织中，低氧（而非缺氧/氧合（HR））可增加sFlt-1表达。此外，绒毛外植体暴露于二甲草酰甘氨酸（一种脯氨酰羟化酶的药理学抑制剂，其通过增加HIF-1 α稳定性来模拟缺氧）增加了sFlt-1表达。相反，使用反义寡核苷酸敲低HIF-1 α，降低sFlt- 1表达。总之，胎盘sFlt-1的表达增加了生理和病理低水平的氧气。这种氧诱导的作用是通过转录因子HIF-1介导的。低氧水平，而不是间歇性的氧张力（HR）的变化，发挥重要作用，在调节sFlt- 1的表达在发展中的人胎盘，因此可能有助于先兆子痫的发展。
Elevated expression of soluble vascular endothelial growth factor receptor-1 (sFlt-1) in preeclampsia plays a major role in the pathogenesis of this serious disorder of human pregnancy. Although reduced placental oxygenation is thought to be involved in the pathogenesis of preeclampsia, it is unclear how oxygen regulates placental sFlt-1 expression. The aims herein were to investigate sFlt-1 expression in in vivo and in vitro physiological and pathological models of human placental hypoxia and to understand the role of hypoxia inducible factor-1 (HIF-1) in regulating the expression of this molecule. sFlt-1 expression in placental villi was significantly increased under physiological low oxygen conditions in early first-trimester and in high-altitude placentae, as well as in pathological low oxygen conditions, such as preeclampsia. In high-altitude and in preeclamptic tissue, sFlt-1 localized within villi to perivascular regions, the syncytiotrophoblast layer, and syncytial knots. In first-trimester villous explants, low oxygen, but not hypoxiareoxygenation (HR), increased sFlt-1 expression. Moreover, exposure of villous explants to dimethyloxalyl-glycin, a pharmacological inhibitor of prolyl-hydroxylases, which mimics hypoxia by increasing HIF-1 alpha stability, increased sFlt-1 expression. Conversely, HIF-1 alpha knockdown using antisense oligonucleotides, decreased sFlt- 1 expression. In conclusion, placental sFlt-1 expression is increased by both physiologically and pathologically low levels of oxygen. This oxygen-induced effect is mediated via the transcription factor HIF-1. Low oxygen levels, as opposed to intermittent oxygen tension (HR) changes, play an important role in regulating sFlt- 1 expression in the developing human placenta and hence may contribute to the development of preeclampsia.