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J Biol Chem. 2016 Apr 8;291(15):8231-40. doi: 10.1074/jbc.M115.707836. Epub 2016 Feb 21.

Sustained Endocannabinoid Signaling Compromises Decidual Function and Promotes Inflammation-induced Preterm Birth.

Author information

1
From the Division of Reproductive Sciences, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229 and xiaofei.sun@cchmc.org.
2
From the Division of Reproductive Sciences, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229 and.
3
Department of Psychological and Brain Sciences, Kinsey Institute for Research in Sex, Gender, and Reproduction, Indiana University, Bloomington, Indiana 47405.
4
From the Division of Reproductive Sciences, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229 and sk.dey@cchmc.org.

Abstract

Recent studies provide evidence that premature maternal decidual senescence resulting from heightened mTORC1 signaling is a cause of preterm birth (PTB). We show here that mice devoid of fatty acid amide hydrolase (FAAH) with elevated levels ofN-arachidonyl ethanolamide (anandamide), a major endocannabinoid lipid mediator, were more susceptible to PTB upon lipopolysaccharide (LPS) challenge. Anandamide is degraded by FAAH and primarily works by activating two G-protein-coupled receptors CB1 and CB2, encoded by Cnr1 and Cnr2, respectively. We found thatFaah(-/-)decidual cells progressively underwent premature senescence as marked by increased senescence-associated β-galactosidase (SA-β-Gal) staining and γH2AX-positive decidual cells. Interestingly, increased endocannabinoid signaling activated MAPK p38, but not p42/44 or mTORC1 signaling, inFaah(-/-)deciduae, and inhibition of p38 halted premature decidual senescence. We further showed that treatment of a long-acting anandamide in wild-type mice at midgestation triggered premature decidual senescence utilizing CB1, since administration of a CB1 antagonist greatly reduced the rate of PTB inFaah(-/-)females exposed to LPS. These results provide evidence that endocannabinoid signaling is critical in regulating decidual senescence and parturition timing. This study identifies a previously unidentified pathway in decidual senescence, which is independent of mTORC1 signaling.

KEYWORDS:

anandamide (N-arachidonoylethanolamine) (AEA); cannabinoid receptor type 1 (CB1); fatty acid metabolism; pregnancy; senescence

PMID:
26900150
PMCID:
PMC4825023
DOI:
10.1074/jbc.M115.707836
[Indexed for MEDLINE]
Free PMC Article

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