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Melatonin prevents preeclamptic sera and antiphospholipid antibodies inducing the production of reactive nitrogen species and extrusion of toxic trophoblastic debris from first trimester placentae |
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| Affiliation: | 1. The Hospital of Obstetrics & Gynaecology, Fudan University, Shanghai, China;2. Department of Obstetrics & Gynaecology, The University of Auckland, New Zealand;3. School of Biological Science, The University of Auckland, New Zealand;1. Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Oxford Road, Manchester M13 9WL, UK;2. The Paul Mellon Laboratory, ‘Brunswick’, 18 Woodditton Road, Newmarket, Suffolk CB8 9BJ, UK;1. Faculty of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan;2. Laboratory of Drug Lifetime Management, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan;3. Interfaculty Initiative in Information Studies, The University of Tokyo, Tokyo, Japan;4. Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan;1. Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China;2. Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China |
| Abstract: | BackgroundThe exact cause of preeclampsia is unknown. However a “toxin” from the placenta triggers the condition via activation of the maternal endothelium. Extracellular vesicles (EVs) from the syncytiotrophoblast, may be an endothelial-activating toxin. Antiphospholipid antibodies (aPL) and preeclamptic sera both induce the production of endothelial cell-activating EVs by mechanisms which may produce excess free-radicals in the placenta. Melatonin is produced by the human placenta and has both direct and indirect anti-free-radical properties and may therefore counter the effects of aPL and preeclamptic sera.MethodsFirst trimester placental explants were exposed to preeclamptic sera or aPL in the presence or absence of melatonin. Nitrosylative damage was assessed in the explants by immunohistochemistry and the effect of EVs from these explants on endothelial cell activation determined by ICAM-1. Release of nitrosylated proteins from the explants was also measured.ResultsPlacental explants showed reduced secretion of melatonin after treatment with preeclamptic sera. Nitrosylated proteins were more abundant in placentae that had been treated with aPL or preeclamptic sera and EVs from such placentae induced endothelial cell activation. Adding melatonin to the aPL or preeclamptic sera reversed the protein nitrosylation and production of endothelial-activating EVs.DiscussionOur data are consistent with reports that the levels of circulating melatonin are reduced in preeclampsia and suggest that aPL and factors in preeclamptic sera induce free-radical-mediated damage in the placenta leading to the production of endothelial-activating EVs. Melatonin reversing production of endothelial-activating EVs indicates that melatonin may have therapeutic benefits in women with preeclampsia and/or aPL. |
| Keywords: | Preeclampsia Antiphospholipid Extracellular vesicles Trophoblastic debris Melatonin Reactive nitrogen species |
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