Underpinning the endocannabinoid 2-AG induced-apoptosis in trophoblast cells: the role of oxidative stress

The endocannabinoid system (ECS) regulates several reproductive events such as decidualization, implantation and placentation. Placental development involves a balance between proliferation, differentiation and cell death of trophoblasts. We have reported that 2-AG induces apoptosis in trophoblast cells [1], on which endoplasmic reticulum (ER)-stress might play a role. Prolonged ER-stress may activate pancreatic ER kinase (PERK) protein and trigger apoptotic pathways. Therefore, in this work it was evaluated the role of PERK branch on 2-AG induced-apoptosis in BeWo cell line, a model of cytotrophoblasts. Through q-PCR it was observed that 2-AG increased mRNA levels of crucial ER-stress markers: CHOP and ATF4. Through Western-blot we found that 2-AG also increased CHOP protein levels and activation/phospohorylation of eIF2α. The involvement of cannabinoid receptors was also investigated. Herein we found that 2-AG induced apoptosis is mediated by activation of PERK branch of ER-stress response which may impair placental development, and lead to miscarriage, fetal growth-restriction and pregnancy-related diseases.