Endocannabinoids participate in placental apoptosis induced by hypoxia inducible factor-1

CAROU C; SEYAHIAN; TRIGUBO D; MARTINEZ N; TORO A; LEGUIZAMÓN GF; FARINA MG; ABÁN C ; ALBAMONTE I; FRANCHI AM ; DAMIANO AE

APOPTOSIS

SPRINGER

Lugar: Berlin; Año: 2016 vol. 10 p. 1094 - 1105

1360-8185

During pregnancy, apoptosis is a physiologicalevent critical in the remodeling and aging of the placenta.Increasing evidence has pointed towards the relevance ofendocannabinoids (ECs) and hypoxia as modulators of trophoblastcell death. However, the relation between thesefactors is still unknown. In this report, we evaluated theparticipation of ECs in placental apoptosis induced by cobaltchloride (CoCl2), a hypoxia mimicking agent that stabilizesthe expression of hypoxia inducible factor-1 alpha (HIF-1a).We found that HIF-1a stabilization decreased FAAHmRNA and protein levels, suggesting an increase in ECstone. Additionally, CoCl2 incubation and Met-AEA treatmentreduced cell viability and increased TUNEL-positivestaining in syncytiotrophoblast layer. Immunohistochemicalanalysis demonstrated Bax and Bcl-2 protein expression inthe cytoplasm of syncytiotrophoblast. Finally, HIF-1a stabilizationproduced an increase in Bax/Bcl-2 ratio, activationof caspase 3 and PARP cleavage. All these changes inapoptotic parameters were reversed with AM251, a CB1antagonist. These results demonstrate that HIF-1a mayinduce apoptosis in human placenta via intrinsic pathway bya mechanism that involves activation of CB1 receptor suggestinga role of the ECs in this process.