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

Objective: To evaluate the effects of the cannabinoid system on the regulation of endometrial stromal cell (ESCs) dynamic behavior. Design: ESC 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. Setting: Molecular research institution. Patient(s): Endometrial tissues were obtained from 40 reproductive-age women undergoing laparoscopy for benign pathologies. Interventions: ESCs were treated with methanadamide and with selective agonist (ACEA) and antagonist (AM251) of the cannabinoid receptor 1. Main Outcome Measures: Cellular 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.