Endocannabinoid system regulates migration of endometrial stromal cells via cannabinoid receptor 1 through the activation of PI3K and ERK1/2 pathways

ObjectiveTo evaluate the effects of the cannabinoid system on the regulation of endometrial stromal cell (ESCs) dynamic behavior.DesignESC migration, electrical signal generated by K+ channels, and cytoskeletal-actin dynamics were evaluated in response to treatment with the synthetic endocannabinoid methanandamide. Selective agonists and antagonists were used to identify both the receptor and the biochemical pathways involved.SettingMolecular research institution.Patient(s)Endometrial tissues were obtained from 40 reproductive-age women undergoing laparoscopy for benign pathologies.InterventionsESCs were treated with methanadamide and with selective agonist (ACEA) and antagonist (AM251) of the cannabinoid receptor 1.Main Outcome MeasuresCellular migration was evaluated by means of chemotaxis experiments in a Boyden chamber. Electric signal generated by K+ channels was evaluated by patch clamp experiments Cellular morphology and cytoskeletal-actin dynamics were evaluated by immunofluorescence.Result(s)Methanandamide enhanced ESC migration via cannabinoid receptor I (CNR1) through the activation of PI3K/Akt and ERK1/2 pathways. The increased ESC migration was associated with cytoskeleton reorganization identified by the dissolution of F-actin stress fibers and the presence of stress fiber arcs and with increased electrical signal generated by K+ channels.Conclusion(s)In physiologic conditions, the cannabinoid system has a central role in regulating endometrial cell migration. The involvement of ERK1/2 and PI3-K/Akt pathways points to a potential role of endocannabinoids in some pathologic conditions characterized by enhanced endometrial cell invasiveness.