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

Area of Science:

• Reproductive biology
• Endocrinology
• Cellular senescence

Background:

• Premature preterm birth (PTB) is linked to maternal decidual senescence.
• Heightened mTORC1 signaling has been implicated in PTB.
• The role of endocannabinoids in regulating parturition timing is not fully understood.

Purpose of the Study:

• To investigate the role of fatty acid amide hydrolase (FAAH) and its substrate, anandamide, in regulating decidual senescence and PTB.
• To elucidate the signaling pathways involved in anandamide-induced decidual senescence.

Main Methods:

• Utilized FAAH-deficient (Faah(-/-)) mice and wild-type mice.
• Administered lipopolysaccharide (LPS) to induce PTB.
• Assessed decidual senescence markers (SA-β-Gal, γH2AX).
• Investigated signaling pathways including MAPK and mTORC1.
• Used CB1 receptor antagonist to block anandamide signaling.

Main Results:

• Faah(-/-) mice exhibited increased susceptibility to LPS-induced PTB.
• Faah(-/-) decidual cells showed premature senescence.
• Anandamide signaling activated p38 MAPK, but not mTORC1, leading to senescence.
• Inhibition of p38 MAPK or CB1 receptor signaling prevented premature decidual senescence and PTB.

Conclusions:

• Endocannabinoid signaling, particularly through the CB1 receptor, is critical for regulating decidual senescence and parturition timing.
• FAAH deficiency and subsequent anandamide accumulation promote PTB via a p38 MAPK-dependent pathway.
• This study identifies a novel, mTORC1-independent pathway in decidual senescence contributing to PTB.