The trophoblast of human placenta forms a syncytium in direct contact with maternal blood. The syncytiotrophoblast (STB) is the main structural and functional epithelial layer required for normal fetal growth and development. Hypoxia inhibit human placental villous syncytialization, however the exact mechanisms remain
unknown. Disturbance in this process may result in pregnancy-associated diseases such as preeclampsia and intrauterine growth restriction. Endogenous cannabinoids (endocannabinoids, ECs) are an emerging group of bioactive lipids mediators which, together with their receptors and the enzymes involved in their metabolism,
constitute the endocannabinoid system (ES). One of the most important endocannabinoids produced by the placenta is anandamide (Narachidonylethanoalmine, AEA). In the present study, we investigated if the endocannabinoid system participates in the impairment of trophoblast syncytialization induced by hypoxia inducible factor 1 (HIF-1). BeWo cell line was cultured with 25μM forskolin (FSK) to induce cell fusion. Cytothophoblast (BeWo) and STB (BeWo + FSK) cells were treated with and without cobalt chloride (CoCl2), a hypoxia-mimetic agent that stabilizes (HIF-1α); or R-(+)-Methanandamide (Met- AEA), a stable anandamide analogous. Cell viability was evaluated by MTT assay. Markers for trophoblast syncytialization: syncytin-1 and glial cells missing-1 (GCM- 1), were analyzed by western blot and RT-PCR, respectively. The distribution of the E-cadherin was studied by immunocytochemistry. Incubation with CoCl2 and Met- AEA significantly reduced cell viability (p<0,05). Treatment with 100μM CoCl2 significantly increased HIF-1α protein levels (p<0,01). Forskolin-induced cell fusion identified by increased levels of GCM-1 mRNA and syncytin-1 protein expression were suppressed with CoCl2 and Met-AEA treatment (p<0,05). Localization of Ecadherin confirmed that forskolin induced cell fusion. In the presence of CoCl2 there was a significant decrease in BeWo cells fusion rate compared to forskolin treatment only. The above results suggest that increased levels of HIF-1 may disturb trophoblast syncytialization and that endocannabinoids could play an important role in this critical process of human placenta.