The cannabinoid receptor CB1contributes to the development of ectopic lesions in a mouse model of endometriosis

Ana-Maria Sanchez, Federica Quattrone, Maria Pannese, Adele Ulisse, Massimo Candiani, Javier Díaz-Alonso, Javier Diaz-Alonso, Guillermo Velasco, Paola Panina-Bordignon, Paola Panina‐Bordignon
Human Reproduction · 2016 · vol. 32(1) , pp. 175–184 · doi:10.1093/humrep/dew281 · PMID:27821707 · W2550635479
article OA: bronze CC0 ⤵ 9 in-corpus citations
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Endocannabinoid signaling via the CB1 receptor promotes ectopic lesion development in a mouse model of endometriosis by upregulating pro-proliferative and pro-invasive genes.

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Abstract

Does signaling via the cannabinoid (CB1) receptor play a role in the pathogenesis of endometriosis in a mouse model? Mice treated with a CB1 agonist developed larger ectopic lesions, while less severe lesions developed in the absence of functional CB1 expression. The expression of components of the endocannabinoid system has been demonstrated in both mouse and human uteri. CB1 receptors are expressed in human epithelial and stromal cell lines derived from eutopic endometrium and deep infiltrating endometriosis nodules. This was a randomized study in a mouse model of endometriosis. In a first set of experiments, mice with endometriosis were treated with the CB1 receptor agonist methanandamide (MET) (5 mg/kg, n = 20) on Days 1–5 and 8–12. In a second set of experiments, endometriosis development was evaluated in CB1−/− mice and in their wild-type (WT) littermates. Endometriosis-like lesions were induced in Balb/c and C57/Bl6 mice. Two weeks after disease induction, the lesions were counted, measured and either included for immunohistochemistry analysis or frozen for gene expression profiling by semi-quantitative real-time PCR. To limit the role of chance, the experiments were conducted under standardized laboratory conditions with appropriate controls. The lesion total volume was significantly higher in MET-treated compared with vehicle-treated mice (P < 0.05). Expression levels of mRNA for survivin, N-cadherin, integrin β1 and interleukin-6 were increased in the ectopic endometrium of MET-treated versus vehicle-treated mice (P < 0.05). CB1−/− recipients that received endometrial tissue fragments from CB1−/− donors, WT recipients that received endometrial tissue fragments from CB1−/− donors and CB1−/− recipients that received endometrial tissue fragments from WT donors all showed a significant reduction in total lesion volume and lower expression of survivin and N-cadherin compared with WT recipients receiving uterine fragments from WT donors (P < 0.05). N/A. We provide evidence that endocannabinoid signaling via CB1 receptor plays a role in the development of endometriosis in a mouse model. However, the relative contribution of the CB1-mediated signaling pathways active in inflammatory, uterine and peritoneal cells remains to be ascertained. Since the study was performed in a mouse model, the significance of the findings in the human system warrants further investigation. Clarifying the function and regulation of CB1 and its molecular interactions with endogenous ligands, and how endocannabinoids levels are regulated in women with endometriosis, represent critical areas of research for the potential development of a novel medical treatment of the disease. A.M.S. was supported by a fellowship from Fondazione Giorgio Pardi. The authors have no conflicts of interest to declare.

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Condition tags

endometriosisdie_deep_infiltrating

MeSH descriptors

Arachidonic Acids Cannabinoid Receptor Agonists Endometriosis Peritoneal Diseases Receptor, Cannabinoid, CB1 Animals Arachidonic Acids Cadherins Cadherins Cannabinoid Receptor Agonists Cell Proliferation Cell Proliferation Disease Models, Animal Endometriosis Endometriosis Endometrium Endometrium Endometrium Endometrium Female

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