Anandamide Modulates NOTCH1 Signalling and Inflammatory Responses During Human Endometrial Stromal Cell Decidualization.

Authors

Ilenia Carriero, Valentina Lacconi, Claudia Bianco, Nicole Bertani, Camilla Stamme, Valeria Gasperi, Micol Massimiani, Carlo Ticconi, Mauro Maccarrone, Gina La Sala, Luisa Campagnolo

Published in

Reproduction (Cambridge, England). Aug 17, 2026. Epub Aug 17, 2026.

Abstract

Successful implantation requires coordinated decidual differentiation of endometrial stromal cells. This study shows that anandamide treatment of decidualising cells is associated with reduced NOTCH1 activation and selective alterations in decidual, inflammatory and structural programs.
Decidualization of endometrial stromal cells is essential for human embryo implantation and pregnancy maintenance. The endocannabinoid system (ECS), particularly anandamide (AEA), has been implicated in endometrial receptivity, but the mechanisms through which AEA influences decidualization have been only partially elucidated. This study investigates the effects of AEA during decidualization of immortalised human endometrial stromal cells (HESCs), focusing on neurogenic locus notch homolog protein 1 (NOTCH1) pathway, inflammatory mediators, cell-cycle arrest/senescence-associated markers and cytoskeletal remodelling. Expression was analysed by qRT-PCR, Western blot, and immunofluorescence. AEA treatment during decidualization selectively reduced forkhead box O1 (FOXO1) and insulin-like growth factor binding protein 1 (IGFBP1) without affecting prolactin (PRL); homeobox A10 (HOXA10) was reduced during decidualization but was not further modified by AEA. AEA also attenuated NOTCH1 activation and reduced HES-related family bHLH transcription factor with YRPW motif 1 (HEY1) expression. Given the role of NOTCH signalling in cellular plasticity and cytoskeletal organization, NOTCH1/HEY1 attenuation after AEA exposure was accompanied by changes in snail family transcriptional repressor 1 (SNAI1), vimentin organization and N-cadherin distribution. Consistent with the inflammatory component of stromal decidualization, decidualized HESCs showed increased interleukin-1 beta (IL1B), interleukin-8/C-X-C motif chemokine ligand 8 (CXCL8/IL-8) and prostaglandin-endoperoxide synthase 2/cyclooxygenase-2 (PTGS2/COX-2), whereas AEA reduced selected inflammatory mediators. Analysis of cyclin-dependent kinase inhibitor 1A (CDKN1A/p21) and cyclin-dependent kinase inhibitor 2A (CDKN2A/p16) suggested a short-term senescence-associated response, with AEA attenuating p21 expression. These findings suggest that AEA interferes with transcriptional and structural pathways critical for decidualization, highlighting a potential role of ECS-NOTCH1 crosstalk in implantation failure and endometrial dysfunction.

PMID:
42606559
Bibliographic data and abstract were imported from PubMed on 18 Aug 2026.

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