PMID- 29778808 OWN - NLM STAT- MEDLINE DCOM- 20190314 LR - 20211214 IS - 1096-1186 (Electronic) IS - 1043-6618 (Linking) VI - 134 DP - 2018 Aug TI - Maternal treatment with a placental-targeted antioxidant (MitoQ) impacts offspring cardiovascular function in a rat model of prenatal hypoxia. PG - 332-342 LID - S1043-6618(18)30102-6 [pii] LID - 10.1016/j.phrs.2018.05.006 [doi] AB - 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 muM) 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. CI - Copyright (c) 2018 Elsevier Ltd. All rights reserved. FAU - Aljunaidy, Mais M AU - Aljunaidy MM AD - 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. FAU - Morton, Jude S AU - Morton JS AD - 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. FAU - Kirschenman, Raven AU - Kirschenman R AD - 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. FAU - Phillips, Tom AU - Phillips T AD - Musculoskeletal Research Unit, University of Bristol, Bristol, BS10 5NB, UK. FAU - Case, C Patrick AU - Case CP AD - Musculoskeletal Research Unit, University of Bristol, Bristol, BS10 5NB, UK. FAU - Cooke, Christy-Lynn M AU - Cooke CM AD - 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. FAU - Davidge, Sandra T AU - Davidge ST AD - 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. Electronic address: sandra.davidge@ualberta.ca. LA - eng GR - Canadian Institutes of Health Research/International PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180517 PL - Netherlands TA - Pharmacol Res JT - Pharmacological research JID - 8907422 RN - 0 (Antioxidants) RN - 0 (Organophosphorus Compounds) RN - 1339-63-5 (Ubiquinone) RN - 47BYS17IY0 (mitoquinone) SB - IM MH - Age Factors MH - Animals MH - Antioxidants/*administration & dosage MH - Cardiovascular Diseases/metabolism/physiopathology/*prevention & control MH - Disease Models, Animal MH - Female MH - Fetal Hypoxia/*drug therapy/metabolism/physiopathology MH - Gestational Age MH - Hemodynamics/drug effects MH - Male MH - Maternal Exposure MH - Myocardial Contraction/drug effects MH - Nanoparticles MH - Organophosphorus Compounds/*administration & dosage MH - Oxidative Stress/*drug effects MH - Placenta/*drug effects/metabolism/physiopathology MH - Pregnancy MH - *Prenatal Exposure Delayed Effects MH - Rats, Sprague-Dawley MH - Sex Factors MH - Ubiquinone/administration & dosage/*analogs & derivatives MH - Ventricular Function, Left/drug effects OTO - NOTNLM OT - Antioxidants OT - Cardiovascular OT - DOHaD OT - Nanoparticles EDAT- 2018/05/21 06:00 MHDA- 2019/03/15 06:00 CRDT- 2018/05/21 06:00 PHST- 2018/01/24 00:00 [received] PHST- 2018/04/17 00:00 [revised] PHST- 2018/05/09 00:00 [accepted] PHST- 2018/05/21 06:00 [pubmed] PHST- 2019/03/15 06:00 [medline] PHST- 2018/05/21 06:00 [entrez] AID - S1043-6618(18)30102-6 [pii] AID - 10.1016/j.phrs.2018.05.006 [doi] PST - ppublish SO - Pharmacol Res. 2018 Aug;134:332-342. doi: 10.1016/j.phrs.2018.05.006. Epub 2018 May 17.