Placental Adaptation to Early-Onset Hypoxic Pregnancy and Mitochondria-Targeted Antioxidant Therapy in a Rodent Model.
Placental Adaptation to Early-Onset Hypoxic Pregnancy and Mitochondria-Targeted Antioxidant Therapy in a Rodent Model.
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DOI：
10.1016/j.ajpath.2018.07.027
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发表时间：
2018-12
期刊：
影响因子：
--
通讯作者：
Giussani DA
中科院分区：
文献类型：
--
作者：
Nuzzo AM;Camm EJ;Sferruzzi-Perri AN;Ashmore TJ;Yung HW;Cindrova-Davies T;Spiroski AM;Sutherland MR;Logan A;Austin-Williams S;Burton GJ;Rolfo A;Todros T;Murphy MP;Giussani DA
胎盘对不利的环境条件作出反应，通过调整其底物转移能力来维持胎儿的生长和发育。早发性缺氧对胎盘形态和未折叠蛋白反应（UPR）激活的影响是通过一个已建立的大鼠模型来确定的，该模型中胎儿生长限制最小化。我们进一步确定了母亲使用线粒体靶向抗氧化剂（MitoQ）治疗是否能在缺氧妊娠期间提供保护。妊娠第6 ~ 20天，Wistar母鼠分别暴露于常氧（21% O2）或低氧（13% ~ 14% O2）环境中，并在饮水中添加或不添加MitoQ （500 μmol/L）。第20天，对动物实施安乐死并称重，对雄性胎儿的胎盘进行体视观察。在冷冻胎盘的其他队列中，用Western blot分析确定UPR激活。低氧妊娠和MitoQ治疗均不影响胎儿生长。低氧增加胎盘体积和胎儿毛细血管表面积，诱导线粒体应激和UPR，葡萄糖调节蛋白78和激活转录因子（ATF） 4蛋白上调证明了这一点。低氧妊娠时，MitoQ治疗可增加胎盘母血空间表面积和体积，阻止线粒体应激和ATF4通路的激活。数据表明，线粒体靶向抗氧化剂可能通过保护胎盘应激和增强胎盘灌注的机制对复杂妊娠有益。
The placenta responds to adverse environmental conditions by adapting its capacity for substrate transfer to maintain fetal growth and development. Early-onset hypoxia effects on placental morphology and activation of the unfolded protein response (UPR) were determined using an established rat model in which fetal growth restriction is minimized. We further established whether maternal treatment with a mitochondria-targeted antioxidant (MitoQ) confers protection during hypoxic pregnancy. Wistar dams were exposed to normoxia (21% O2) or hypoxia (13% to 14% O2) from days 6 to 20 of pregnancy with and without MitoQ treatment (500 μmol/L in drinking water). On day 20, animals were euthanized and weighed, and the placentas from male fetuses were processed for stereology to assess morphology. UPR activation in additional cohorts of frozen placentas was determined with Western blot analysis. Neither hypoxic pregnancy nor MitoQ treatment affected fetal growth. Hypoxia increased placental volume and the fetal capillary surface area and induced mitochondrial stress as well as the UPR, as evidenced by glucose-regulated protein 78 and activating transcription factor (ATF) 4 protein up-regulation. MitoQ treatment in hypoxic pregnancy increased placental maternal blood space surface area and volume and prevented the activation of mitochondrial stress and the ATF4 pathway. The data suggest that mitochondria-targeted antioxidants may be beneficial in complicated pregnancy via mechanisms protecting against placental stress and enhancing placental perfusion.
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