TY - JOUR
T1 - Fetal Exosomal Platelet-activating Factor Triggers Functional Progesterone Withdrawal in Human Placenta
AU - Palomares, Kristy T.
AU - Parobchak, Nataliya
AU - Ithier, Mayra Cruz
AU - Aleksunes, Lauren M.
AU - Castaño, Paula M.
AU - So, Melody
AU - Faro, Revital
AU - Heller, Debra
AU - Wang, Bingbing
AU - Rosen, Todd
N1 - Publisher Copyright:
© 2020, Society for Reproductive Investigation.
PY - 2021/1
Y1 - 2021/1
N2 - 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.
AB - 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.
KW - Exosomes
KW - Fetal cord blood
KW - NF-kappaB
KW - Platelet-activating factor
KW - Progesterone receptor-A
KW - methylation
KW - placenta
KW - pro-labor genes
UR - https://www.scopus.com/pages/publications/85089311593
U2 - 10.1007/s43032-020-00283-7
DO - 10.1007/s43032-020-00283-7
M3 - Article
C2 - 32780361
AN - SCOPUS:85089311593
SN - 1933-7191
VL - 28
SP - 252
EP - 262
JO - Reproductive Sciences
JF - Reproductive Sciences
IS - 1
ER -