Nrf2 inactivation enhances placental angiogenesis in a preeclampsia mouse model and improves maternal and fetal outcomes
Nrf2 inactivation enhances placental angiogenesis in a preeclampsia mouse model and improves maternal and fetal outcomes
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DOI：
10.1126/scisignal.aam5711
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发表时间：
2017-05-16
影响因子：
7.3
通讯作者：
Yamamoto, Masayuki
中科院分区：
文献类型：
--
作者：
Nezu, Masahiro;Souma, Tomokazu;Yamamoto, Masayuki
胎盘激活的肾素-血管紧张素系统（RAS）在先兆子痫的发病机制中起着关键作用。活性氧（ROS）被认为影响胎盘血管生成，这对于预防先兆子痫病理至关重要。我们在RAS诱导的先兆子痫小鼠模型中，通过基因修饰Keap 1-Nrf 2通路（一种细胞抗氧化防御系统），研究了ROS在先兆子痫中的作用。Nrf 2缺陷会损害细胞的抗氧化反应，然而，Nrf 2缺陷在先兆子痫小鼠改善母体和胎儿的生存，改善宫内生长迟缓，并增加氧化DNA损伤。此外，Nrf 2缺陷小鼠的胎盘具有增加的内皮细胞增殖和致密的血管网络。相比之下，Nrf 2过度活跃的先兆子痫小鼠的胎盘显示出抑制的血管生成，这与编码血管生成趋化因子和细胞因子的基因表达减少有关。我们的研究结果支持了ROS介导的信号传导对于维持先兆子痫胎盘血管生成至关重要的观点，并可能为先兆子痫抗氧化剂临床试验的负面结果提供机制性见解。
Placental activation of the renin-angiotensin system (RAS) plays a key role in the pathogenesis of preeclampsia. Reactive oxygen species (ROS) are thought to affect placental angiogenesis, which is critical for preventing preeclampsia pathology. We examined the role of ROS in preeclampsia by genetically modifying the Keap1-Nrf2 pathway, a cellular antioxidant defense system, in a mouse model of RAS-induced preeclampsia. Nrf2 deficiency would be expected to impair cellular antioxidant responses; however, Nrf2 deficiency in preeclamptic mice improved maternal and fetal survival, ameliorated intra-uterine growth retardation, and augmented oxidative DNA damage. Furthermore, the placentas of Nrf2-deficient mice had increased endothelial cell proliferation with dense vascular networks. In contrast, the placentas of preeclamptic mice with overactive Nrf2 showed repressed angiogenesis, which was associated with decreased expression of genes encoding angiogenic chemokines and cytokines. Our findings support the notion that ROS-mediated signaling is essential for maintaining placental angiogenesis in preeclampsia and may provide mechanistic insight into the negative results of clinical trials for antioxidants in preeclampsia.