Maternal treatment with a placental-targeted antioxidant (MitoQ) impacts offspring cardiovascular function in a rat model of prenatal hypoxia
Maternal treatment with a placental-targeted antioxidant (MitoQ) impacts offspring cardiovascular function in a rat model of prenatal hypoxia
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DOI：
10.1016/j.phrs.2018.05.006
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发表时间：
2018-08-01
影响因子：
9.3
通讯作者：
Davidge, Sandra T.
中科院分区：
文献类型：
--
作者：
Aljunaidy, Mais M.;Morton, Jude S.;Davidge, Sandra T.
宫内生长受限是产前缺氧的常见后果，是胎儿发病和死亡的主要原因，对人口健康有重大影响。缺氧可能会增加胎盘氧化应激，并导致胎盘衍生因子的异常释放，这些因子正在成为发育编程的潜在贡献者。纳米颗粒连接的药物正在成为一种新的方法，以提供针对胎盘的治疗，并避免直接暴露于胎儿的风险。我们假设，胎盘治疗与抗氧化剂MitoQ加载到纳米粒子（nMitoQ）将防止暴露于产前缺氧的后代心血管疾病的发展。妊娠大鼠在妊娠第15天（GD）静脉注射生理盐水或nMitoQ（125 μ M），并从GD 15 -21（期限：22天）暴露于常氧（21% O-2）或缺氧（11% O-2）。在一组动物中，在GD 21对大鼠实施安乐死，以评估胎仔体重、胎盘重量和胎盘氧化应激。在另一组动物中，允许母鼠在正常大气条件下分娩（术语：GD 22），并在7和13月龄时评估雄性和雌性后代的体内心脏功能（超声心动图）和血管功能（钢丝肌电图，肠系膜动脉）。缺氧增加了男性和女性胎儿胎盘中的氧化应激，nMitoQ可以预防这种情况。暴露于产前缺氧的7个月大的雄性和雌性后代表现出心脏舒张功能障碍，其中nMitoQ仅在7个月大的雌性后代中改善。暴露于产前缺氧的13个月大雌性后代的血管对乙酰甲胆碱的敏感性降低，而nMitoQ治疗改善了对照组和缺氧暴露雌性后代的血管舒张。暴露于缺氧的13个月大的雄性后代显示出与年龄相关的血管对苯丙氨酸敏感性降低，这是由nMitoQ预防的。总之，子宫内胎盘靶向MitoQ治疗对成年后代心血管功能具有有益的性别和年龄依赖性影响。
Intrauterine growth restriction, a common consequence of prenatal hypoxia, is a leading cause of fetal morbidity and mortality with a significant impact on population health. Hypoxia may increase placental oxidative stress and lead to an abnormal release of placental-derived factors, which are emerging as potential contributors to developmental programming. Nanoparticle-linked drugs are emerging as a novel method to deliver therapeutics targeted to the placenta and avoid risking direct exposure to the fetus. We hypothesize that placental treatment with antioxidant MitoQ loaded onto nanoparticles (nMitoQ) will prevent the development of cardiovascular disease in offspring exposed to prenatal hypoxia. Pregnant rats were intravenously injected with saline or nMitoQ (125 mu M) on gestational day (GD) 15 and exposed to either normoxia (21% O-2) or hypoxia (11% O-2) from GD15-21 (term: 22 days). In one set of animals, rats were euthanized on GD 21 to assess fetal body weight, placental weight and placental oxidative stress. In another set of animals, dams were allowed to give birth under normal atmospheric conditions (term: GD 22) and male and female offspring were assessed at 7 and 13 months of age for in vivo cardiac function (echocardiography) and vascular function (wire myography, mesenteric artery). Hypoxia increased oxidative stress in placentas of male and female fetuses, which was prevented by nMitoQ. 7-month-old male and female offspring exposed to prenatal hypoxia demonstrated cardiac diastolic dysfunction, of which nMitoQ improved only in 7-month-old female offspring. Vascular sensitivity to methacholine was reduced in 13-month-old female offspring exposed to prenatal hypoxia, while nMitoQ treatment improved vasorelaxation in both control and hypoxia exposed female offspring. Male 13-month-old offspring exposed to hypoxia showed an age-related decrease in vascular sensitivity to phenylephrine, which was prevented by nMitoQ. In summary, placental-targeted MitoQ treatment in utero has beneficial sex- and age-dependent effects on adult offspring cardiovascular function.