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Disruption of endoplasmic reticulum (ER) homeostasis has been associated with several reproductive pathologies including recurrent pregnancy loss and preeclampsia. In the unfolded protein response (UPR), specific ER-stress signalling pathways are activated to restore ER homeostasis, but if the adaptive response fails, apoptosis is triggered. Protein kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1) and Activating transcription factor 6 (ATF6) are central players in UPR and in ER-stress-induced apoptosis, as well as downstream transcription factors, as C\/EBP homologous protein (CHOP). Our previous studies have shown that the endocannabinoid 2-arachidonoylglycerol (2-AG) modulates trophoblast cell turnover. Nevertheless, the role of ER-stress on 2-AG induced apoptosis and cannabinoid signalling in trophoblast has never been addressed. In this work, we used BeWo cells and human primary cytotrophoblasts isolated from term-placenta. The expression of ER-stress markers was analysed by qRT-PCR and Western blotting. ROS generation was assessed by fluorometric methods, while apoptosis was detected by the evaluation of caspase -3\/-7 activities and Poly (ADP-ribose) polymerase (PARP) cleavage. Our findings indicate that 2-AG is able to induce ER-stress and apoptosis. Moreover, the eukaryotic initiation factor 2 (eIF2\u03b1)\/CHOP pathway involved in ER-stress-induced apoptosis is triggered through a mechanism dependent on cannabinoid receptor CB2 activation. The results bring novel insights on the importance of ER-stress and cannabinoid signalling on 2-AG mechanisms of action in placenta.<\/jats:p>","DOI":"10.1530\/rep-19-0539","type":"journal-article","created":{"date-parts":[[2020,5,1]],"date-time":"2020-05-01T12:16:48Z","timestamp":1588335408000},"page":"171-180","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-11","source":"Crossref","is-referenced-by-count":22,"title":["The endocannabinoid 2-arachidonoylglycerol promotes endoplasmic reticulum stress in placental cells"],"prefix":"10.1093","volume":"160","author":[{"given":"Marta","family":"Almada","sequence":"first","affiliation":[{"name":"UCIBIO , REQUIMTE, Departamento de Ci\u00eancias Biol\u00f3gicas, Laborat\u00f3rio de Bioqu\u00edmica, Faculdade de Farm\u00e1cia, Universidade do Porto, Porto, Portugal"}]},{"given":"Lia","family":"Costa","sequence":"additional","affiliation":[{"name":"UCIBIO , REQUIMTE, Departamento de Ci\u00eancias Biol\u00f3gicas, Laborat\u00f3rio de Bioqu\u00edmica, Faculdade de Farm\u00e1cia, Universidade do Porto, Porto, Portugal"},{"name":"Departamento de Biologia , Universidade de Aveiro, Aveiro, Portugal"}]},{"given":"Bruno","family":"Fonseca","sequence":"additional","affiliation":[{"name":"UCIBIO , REQUIMTE, Departamento de Ci\u00eancias Biol\u00f3gicas, Laborat\u00f3rio de Bioqu\u00edmica, Faculdade de Farm\u00e1cia, Universidade do Porto, Porto, Portugal"}]},{"given":"Patr\u00edcia","family":"Alves","sequence":"additional","affiliation":[{"name":"UCIBIO , REQUIMTE, Departamento de Ci\u00eancias Biol\u00f3gicas, Laborat\u00f3rio de Bioqu\u00edmica, Faculdade de Farm\u00e1cia, Universidade do Porto, Porto, Portugal"}]},{"given":"Jorge","family":"Braga","sequence":"additional","affiliation":[{"name":"Departamento da Mulher e da Medicina Reprodutiva , Servi\u00e7o de Obstetr\u00edcia, Centro Materno-Infantil do Norte Dr Albino Aroso, Centro Hospitalar Universit\u00e1rio do Porto, Porto, Portugal"}]},{"given":"Daniela","family":"Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"Departamento da Mulher e da Medicina Reprodutiva , Servi\u00e7o de Obstetr\u00edcia, Centro Materno-Infantil do Norte Dr Albino Aroso, Centro Hospitalar Universit\u00e1rio do Porto, Porto, Portugal"}]},{"given":"Nat\u00e9rcia","family":"Teixeira","sequence":"additional","affiliation":[{"name":"UCIBIO , REQUIMTE, Departamento de Ci\u00eancias Biol\u00f3gicas, Laborat\u00f3rio de Bioqu\u00edmica, Faculdade de Farm\u00e1cia, Universidade do Porto, Porto, Portugal"}]},{"given":"Georgina","family":"Correia-da-Silva","sequence":"additional","affiliation":[{"name":"UCIBIO , REQUIMTE, Departamento de Ci\u00eancias Biol\u00f3gicas, Laborat\u00f3rio de Bioqu\u00edmica, Faculdade de Farm\u00e1cia, Universidade do Porto, Porto, 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