title: Sustained Endocannabinoid Signaling Compromises Decidual Function and Promotes Inflammation-induced Preterm Birth.
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.
authors.affiliation: From the Division of Reproductive Sciences, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229 and xiaofei.sun@cchmc.org.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Sun
authors.affiliation: From the Division of Reproductive Sciences, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229 and.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Deng
authors.affiliation: From the Division of Reproductive Sciences, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229 and.
authors.forename: Yingju
authors.initials: Y
authors.lastname: Li
authors.affiliation: From the Division of Reproductive Sciences, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229 and.
authors.forename: Shuang
authors.initials: S
authors.lastname: Tang
authors.affiliation: Department of Psychological and Brain Sciences, Kinsey Institute for Research in Sex, Gender, and Reproduction, Indiana University, Bloomington, Indiana 47405.
authors.forename: Emma
authors.initials: E
authors.lastname: Leishman
authors.affiliation: Department of Psychological and Brain Sciences, Kinsey Institute for Research in Sex, Gender, and Reproduction, Indiana University, Bloomington, Indiana 47405.
authors.forename: Heather B
authors.initials: HB
authors.lastname: Bradshaw
authors.affiliation: From the Division of Reproductive Sciences, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229 and sk.dey@cchmc.org.
authors.forename: Sudhansu K
authors.initials: SK
authors.lastname: Dey
mesh_terms: D000581:Amidohydrolases / Q000235:genetics / Q000276:immunology; D000818:Animals; D001095:Arachidonic Acids / Q000276:immunology*; D002478:Cells, Cultured; D003656:Decidua / Q000166:cytology / Q000276:immunology; D063388:Endocannabinoids / Q000276:immunology*; D005260:Female; D017353:Gene Deletion; D007249:Inflammation / Q000150:complications* / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D053284:Polyunsaturated Alkamides / Q000276:immunology*; D047928:Premature Birth / Q000209:etiology* / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001095:Arachidonic Acids; D063388:Endocannabinoids; D008070:Lipopolysaccharides; D053284:Polyunsaturated Alkamides; D000099252:Fatty Acid Amide Hydrolases; C078814:anandamide
keywords: anandamide (N-arachidonoylethanolamine) (AEA); cannabinoid receptor type 1 (CB1); fatty acid metabolism; pregnancy; senescence