Yike Yang1,2,3, Ping Xu1,2,3, Fangyu Zhu1,2,3, Jiujiang Liao1,2,3, Yue Wu1,2,3, Mingyu Hu1,2,3, Huijia Fu1,2,3, Juan Qiao1,2,3, Li Lin1,2,3, Biao Huang1,2,3, Huili Jin1,2,3, Xiyao Liu1,2,3, Yangxi Zheng1,2,3, Li Wen1,2,3, Richard Saffery4,5, Mark D Kilby6,7, Jianying Yan8, Louise C Kenny9, Hongbo Qi1,2,3,8, Chao Tong1,2,3, Philip N Baker1,10. 1. Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. 2. International Collaborative Joint Laboratory of Reproduction and Development of Ministry of Education P.R.C., Chongqing, China. 3. State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, Chongqing, China. 4. Cancer, Disease and Developmental Epigenetics, Murdoch Children's Research Institute, Melbourne, Australia. 5. Department of Pediatrics, University of Melbourne, Melbourne, Australia. 6. Institute of Metabolism and System Research, University of Birmingham, Birmingham, United Kingdom. 7. Fetal Medicine Centre, Birmingham Women's & Children's Foundation Trust, Birmingham, United Kingdom. 8. Fujian Provincial Maternity and Children's Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, China. 9. Department of Women's and Children's Health, Faculty of Health and Life Sciences, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom. 10. College of Life Sciences, University of Leicester, Leicester, United Kingdom.
Abstract
Aims: Although preeclampsia (PE) has been attributed to excessive oxidative stress (OS) in the placenta, mild antioxidants failed to prevent PE in clinical trials. As mitochondria are a major source of OS, this study assessed the potential of a potent mitochondria-targeting antioxidant MitoQ in the prevention of PE. Results: Placentas from women with PE and from reduced uterine perfusion pressure (RUPP) mice demonstrated significantly higher OS, along with increased mitochondrial damage and compromised glutathione peroxidase (GPx) activities. MitoQ administration during late gestation alleviated RUPP-induced PE; whereas early-pregnancy MitoQ treatment not only exacerbated blood pressure, fetal growth restriction, and proteinuria but also reduced the labyrinth/spongiotrophoblast ratio and blood sinuses in the labyrinth. Invasion (Matrigel transwell) and migration (wound healing assay) of trophoblasts were greatly improved by 1 μM hydrogen peroxide (H2O2), but this improvement was abolished by MitoQ or MitoTempo. Mild OS enhanced the expression of miR-29b-3p, which regulates five genes involved in viability and mobility, in HTR8-S/Vneo cells. Innovation and Conclusions: Although the potent mitochondrial-targeting antioxidant MitoQ protects against hypertension and kidney damage induced by RUPP in mice when administered in late gestation, it exacerbates the PE-like phenotype when given in early gestation by interfering with placenta formation because mild OS is required to stimulate trophoblast proliferation, invasion, and migration. Eliminating trophoblastic OS during early pregnancy may lead to compromised placentation and a risk of diseases of placental origin. Therefore, antioxidant therapy for pregnant women should be carefully considered.
Aims: Although preeclampsia (PE) has been attributed to excessive oxidative stress (OS) in the placenta, mild antioxidants failed to prevent PE in clinical trials. As mitochondria are a major source of OS, this study assessed the potential of a potent mitochondria-targeting antioxidant MitoQ in the prevention of PE. Results: Placentas from women with PE and from reduced uterine perfusion pressure (RUPP) mice demonstrated significantly higher OS, along with increased mitochondrial damage and compromised glutathione peroxidase (GPx) activities. MitoQ administration during late gestation alleviated RUPP-induced PE; whereas early-pregnancy MitoQ treatment not only exacerbated blood pressure, fetal growth restriction, and proteinuria but also reduced the labyrinth/spongiotrophoblast ratio and blood sinuses in the labyrinth. Invasion (Matrigel transwell) and migration (wound healing assay) of trophoblasts were greatly improved by 1 μM hydrogen peroxide (H2O2), but this improvement was abolished by MitoQ or MitoTempo. Mild OS enhanced the expression of miR-29b-3p, which regulates five genes involved in viability and mobility, in HTR8-S/Vneo cells. Innovation and Conclusions: Although the potent mitochondrial-targeting antioxidant MitoQ protects against hypertension and kidney damage induced by RUPP in mice when administered in late gestation, it exacerbates the PE-like phenotype when given in early gestation by interfering with placenta formation because mild OS is required to stimulate trophoblast proliferation, invasion, and migration. Eliminating trophoblastic OS during early pregnancy may lead to compromised placentation and a risk of diseases of placental origin. Therefore, antioxidant therapy for pregnant women should be carefully considered.