, Volume 22, Issue 6, pp 816–826 | Cite as

Anandamide oxidative metabolism-induced endoplasmic reticulum stress and apoptosis

  • M. Almada
  • B. M. Fonseca
  • C. Amaral
  • M. Diniz-da-Costa
  • G. Correia-da-Silva
  • N. Teixeira


The Endocannabinoid System (ECS) has been recognized as a crucial player in human reproduction. Changes in the levels of anandamide (AEA), the main endocannabinoid (eCB), negatively affect reproductive events, such as implantation, decidualization and placentation. Cyclooxygenase-2 (COX-2) is a major enzyme expressed in the endometrium and its involvement in female reproductive system has evolved over the last few years. Currently, COX-2 oxidative metabolism is emerging as a key mediator of AEA-induced actions. In this study, we aimed to disclose the mechanisms underlying the effects of AEA in human endometrial stromal cell fate, using a human-derived endometrial cell line (St-T1b). We found that AEA has an anti-proliferative activity through a direct effect on cell cycle progression by inducing G2/M arrest. Moreover, high levels of AEA increased COX-2 activity, triggering apoptotic cell death, with loss of mitochondrial membrane potential, induction of caspase -9 and -3/-7 activities, and cleavage of poly (ADP-ribose) polymerase (PARP). In addition, the involvement of intracellular reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress was verified. These effects were prevented by pre-incubation with a selective COX-2 inhibitor. Therefore, we hypothesize that, in response to altered levels of this eCB, COX-2 oxidative metabolism of AEA may deregulate endometrial cell turnover and, consequently, interfere with cellular events crucial for implantation and decidualization, with a negative impact on human fertility.


Anandamide Apoptosis Human endometrial stromal cells 



The authors thank Fundação para a Ciência e Tecnologia (FCT) for the grant attributed to Almada M (SFRH/BD/81561/2011), Fonseca BM (SFRH/BPD/72958/2010) and Cristina Amaral (SFRH/BPD/98304/2013). The authors also thank to Joana Macedo for helping with the graphic design.


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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • M. Almada
    • 1
  • B. M. Fonseca
    • 1
  • C. Amaral
    • 1
  • M. Diniz-da-Costa
    • 1
  • G. Correia-da-Silva
    • 1
  • N. Teixeira
    • 1
  1. 1.UCIBIO, REQUIMTE, Laboratory of Biochemistry, Department of Biological Sciences, Faculty of PharmacyUniversity of PortoPortoPortugal

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