Aljunaidy Mais M, Morton Jude S, Kirschenman Raven, Phillips Tom, Case C Patrick, Cooke Christy-Lynn M, Davidge Sandra T
Department of Physiology, University of Alberta, Edmonton, T6G 2S2, Canada; Department of Obstetrics and Gynecology, University of Alberta, Edmonton, T6G 2S2, Canada; Women and Children's Health Research Institute and the Cardiovascular Research Centre, Edmonton, T6G 2S2, Canada.
Department of Obstetrics and Gynecology, University of Alberta, Edmonton, T6G 2S2, Canada; Women and Children's Health Research Institute and the Cardiovascular Research Centre, Edmonton, T6G 2S2, Canada.
Pharmacol Res. 2018 Aug;134:332-342. doi: 10.1016/j.phrs.2018.05.006. Epub 2018 May 17.
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 μM) on gestational day (GD) 15 and exposed to either normoxia (21% O) or hypoxia (11% O) 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.
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，对人群健康有重大影响。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，这些因子正逐渐成为发育编程的潜在因素。纳米颗粒连接药物正在成为一种新型的给药方法，可将治疗药物靶向输送至胎盘，避免直接暴露于胎儿的风险。我们假设，用负载有抗氧化剂MitoQ的纳米颗粒（nMitoQ）进行胎盘治疗将预防暴露于产前缺氧的后代患心血管疾病。在妊娠第15天，给怀孕大鼠静脉注射生理盐水或nMitoQ（125μM），并在妊娠第15天至21天（足月：22天）使其暴露于常氧（21% O）或缺氧（11% O）环境。在一组动物中，在妊娠第21天对大鼠实施安乐死，以评估胎儿体重、胎盘重量和胎盘氧化应激。在另一组动物中，让母鼠在正常大气条件下分娩（足月：妊娠第22天），并在雄性和雌性后代7个月和13个月大时评估其体内心脏功能（超声心动图）和血管功能（线肌张力测定法，肠系膜动脉）。缺氧增加了雄性和雌性胎儿胎盘的氧化应激，而nMitoQ可预防这种情况。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有所改善。暴露于产前缺氧的13个月大的雌性后代对乙酰甲胆碱的血管敏感性降低，而nMitoQ治疗改善了对照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对去氧肾上腺素的血管敏感性随年龄下降，而nMitoQ可预防这种情况。总之，子宫内靶向胎盘的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。
