PMID- 31178743 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20231012 IS - 1664-042X (Print) IS - 1664-042X (Electronic) IS - 1664-042X (Linking) VI - 10 DP - 2019 TI - Sex-Specific Effects of Nanoparticle-Encapsulated MitoQ (nMitoQ) Delivery to the Placenta in a Rat Model of Fetal Hypoxia. PG - 562 LID - 10.3389/fphys.2019.00562 [doi] LID - 562 AB - Pregnancy complications associated with chronic fetal hypoxia have been linked to the development of adult cardiovascular disease in the offspring. Prenatal hypoxia has been shown to increase placental oxidative stress and impair placental function in a sex-specific manner, thereby affecting fetal development. As oxidative stress is central to placental dysfunction, we developed a placenta-targeted treatment strategy using the antioxidant MitoQ encapsulated into nanoparticles (nMitoQ) to reduce placental oxidative/nitrosative stress and improve placental function without direct drug exposure to the fetus in order to avoid off-target effects during development. We hypothesized that, in a rat model of prenatal hypoxia, nMitoQ prevents hypoxia-induced placental oxidative/nitrosative stress, promotes angiogenesis, improves placental morphology, and ultimately improves fetal oxygenation. Additionally, we assessed whether there were sex differences in the effectiveness of nMitoQ treatment. Pregnant rats were intravenously injected with saline or nMitoQ (100 mul of 125 muM) on gestational day (GD) 15 and exposed to either normoxia (21% O(2)) or hypoxia (11% O(2)) from GD15 to 21. On GD21, placentae from both sexes were collected for detection of superoxide, nitrotyrosine, nitric oxide, CD31 (endothelial cell marker), and fetal blood spaces, Vegfa and Igf2 mRNA expression in the placental labyrinth zone. Prenatal hypoxia decreased male fetal weight, which was not changed by nMitoQ treatment; however, placental efficiency (fetal/placental weight ratio) decreased by hypoxia and was increased by nMitoQ in both males and females. nMitoQ treatment reduced the prenatal hypoxia-induced increase in placental superoxide levels in both male and female placentae but improved oxygenation in only female placentae. Nitrotyrosine levels were increased in hypoxic female placentae and were reduced by nMitoQ. Prenatal hypoxia reduced placental Vegfa and Igf2 expression in both sexes, while nMitoQ increased Vegfa and Igf2 expression only in hypoxic female placentae. In summary, our study suggests that nMitoQ treatment could be pursued as a potential preventative strategy against placental oxidative stress and programming of adult cardiovascular disease in offspring exposed to hypoxia in utero. However, sex differences need to be taken into account when developing therapeutic strategies to improve fetal development in complicated pregnancies, as nMitoQ treatment was more effective in placentae from females than males. FAU - Ganguly, Esha AU - Ganguly E AD - Department of Physiology, University of Alberta, Edmonton, AB, Canada. AD - Department of Obstetrics and Gynaecology, University of Alberta, Edmonton, AB, Canada. AD - Women and Children's Health Research Institute, University of Alberta, Edmonton, AB, Canada. FAU - Aljunaidy, Mais M AU - Aljunaidy MM AD - Department of Physiology, University of Alberta, Edmonton, AB, Canada. AD - Department of Obstetrics and Gynaecology, University of Alberta, Edmonton, AB, Canada. AD - Women and Children's Health Research Institute, University of Alberta, Edmonton, AB, Canada. FAU - Kirschenman, Raven AU - Kirschenman R AD - Department of Obstetrics and Gynaecology, University of Alberta, Edmonton, AB, Canada. AD - Women and Children's Health Research Institute, University of Alberta, Edmonton, AB, Canada. FAU - Spaans, Floor AU - Spaans F AD - Department of Obstetrics and Gynaecology, University of Alberta, Edmonton, AB, Canada. AD - Women and Children's Health Research Institute, University of Alberta, Edmonton, AB, Canada. FAU - Morton, Jude S AU - Morton JS AD - Department of Obstetrics and Gynaecology, University of Alberta, Edmonton, AB, Canada. AD - Women and Children's Health Research Institute, University of Alberta, Edmonton, AB, Canada. FAU - Phillips, Thomas E J AU - Phillips TEJ AD - Dementia Research Institute, Cardiff University, Cardiff, United Kingdom. FAU - Case, C Patrick AU - Case CP AD - Musculoskeletal Research Unit, University of Bristol, Bristol, United Kingdom. FAU - Cooke, Christy-Lynn M AU - Cooke CM AD - Department of Obstetrics and Gynaecology, University of Alberta, Edmonton, AB, Canada. AD - Women and Children's Health Research Institute, University of Alberta, Edmonton, AB, Canada. FAU - Davidge, Sandra T AU - Davidge ST AD - Department of Physiology, University of Alberta, Edmonton, AB, Canada. AD - Department of Obstetrics and Gynaecology, University of Alberta, Edmonton, AB, Canada. AD - Women and Children's Health Research Institute, University of Alberta, Edmonton, AB, Canada. LA - eng PT - Journal Article DEP - 20190524 PL - Switzerland TA - Front Physiol JT - Frontiers in physiology JID - 101549006 PMC - PMC6543892 OTO - NOTNLM OT - MitoQ OT - hypoxia OT - nanoparticles OT - placenta OT - sex difference EDAT- 2019/06/11 06:00 MHDA- 2019/06/11 06:01 PMCR- 2019/05/24 CRDT- 2019/06/11 06:00 PHST- 2019/03/04 00:00 [received] PHST- 2019/04/24 00:00 [accepted] PHST- 2019/06/11 06:00 [entrez] PHST- 2019/06/11 06:00 [pubmed] PHST- 2019/06/11 06:01 [medline] PHST- 2019/05/24 00:00 [pmc-release] AID - 10.3389/fphys.2019.00562 [doi] PST - epublish SO - Front Physiol. 2019 May 24;10:562. doi: 10.3389/fphys.2019.00562. eCollection 2019.