Fetal Exosomal Platelet-activating Factor Triggers Functional Progesterone Withdrawal in Human Placenta.

Autor: Palomares KT; Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Maternal-Fetal Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, 08901, USA.; Department of Obstetrics and Gynecology, Saint Peter's University Hospital, New Brunswick, NJ, 08901, USA., Parobchak N; Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Maternal-Fetal Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, 08901, USA., Ithier MC; Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Maternal-Fetal Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, 08901, USA., Aleksunes LM; Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, 08854, USA., Castaño PM; Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY, 10032, USA., So M; Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Maternal-Fetal Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, 08901, USA., Faro R; Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Maternal-Fetal Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, 08901, USA.; Department of Obstetrics and Gynecology, Saint Peter's University Hospital, New Brunswick, NJ, 08901, USA., Heller D; Department of Pathology and Laboratory Medicine, Rutgers New Jersey Medical School, Newark, NJ, 07103, USA., Wang B; Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Maternal-Fetal Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, 08901, USA. wangbi@rwjms.rutgers.edu., Rosen T; Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Maternal-Fetal Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, 08901, USA. rosentj@rwjms.rutgers.edu.
Jazyk: angličtina
Zdroj: Reproductive sciences (Thousand Oaks, Calif.) [Reprod Sci] 2021 Jan; Vol. 28 (1), pp. 252-262. Date of Electronic Publication: 2020 Aug 11.
DOI: 10.1007/s43032-020-00283-7
Abstrakt: In most mammals, labor is heralded by the withdrawal of progesterone. In humans, circulating progesterone levels increase as gestation advances while placental expression of progesterone receptor A (PR-A) declines. As a result of PR-A downregulation, the non-canonical NF-κB pathway is activated, an event implicated in triggering labor. Here, we sought to identify fetal-derived mediator(s) that represses placental PR-A in human placenta leading to activation of pro-labor signaling. Lipidomic profiling demonstrated enrichment of platelet-activating factor (PAF) in exosomes originating from the human fetus. Exposure of primary cytotrophoblasts to fetal exosomes from term pregnancies reduced PR-A expression by > 50%, and PAF also reduced PR-A message levels in a dose-dependent manner. Notably, fetal exosomes from preterm pregnancies had lower PAF levels and no effect on PR-A expression. Synthetic PAF-induced DNA methylation increases by 20% at the PR-A promoter, leading to recruitment of corepressors and downregulation of PR-A in cytotrophoblast. Furthermore, suppression of PR-A by PAF-stimulated expression of the pro-labor genes, corticotropin-releasing hormone (CRH) and cyclooxygenase-2 (COX-2), which was reversed by disruption of the DNA methyltransferases 3B and 3L. Taken together, PAF represents a novel fetal-derived candidate for initiation of labor by stimulating methylation and repression of PR-A and activating pro-labor signaling in trophoblast.
Databáze: MEDLINE
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