The endocannabinoid anandamide impairs in vitro decidualization of human cells

Almada, Marta; Amaral, Cristina; Diniz-da-Costa, Maria; Correia-da-Silva, Georgina; Teixeira, Natércia; Fonseca, Bruno M.

doi:10.1530/rep-16-0364

Cited by 35 publications

(15 citation statements)

References 31 publications

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“…When AEA levels are impaired, a miscarriage or ectopic pregnancy can occur (Maccarrone et al 2000), (Wang et al 2004). In addition, we have previously described the disruptive effects of AEA in decidualization (Almada et al 2016), as well as in placental endocrine function (Costa et al 2015a, b, c).…”

Section: Introductionmentioning

confidence: 98%

Effects of cannabis tetrahydrocannabinol on endocannabinoid homeostasis in human placenta

et al. 2019

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Cannabis use has become a hot topic in several countries due to the debate about its legalization for medical purposes. However, data are limited regarding adverse events, safety and potential impact on reproductive health. Cannabis consumption during pregnancy has been associated with gestational disorders such as preterm birth, intrauterine growth restriction, low birth weight and increased risk of miscarriage, though the underlying biochemical mechanisms are still unknown. Given that the endocannabinoid system (ECS) is involved in several reproductive processes, we tested the hypothesis that the negative outcomes may result from the impact on the ECS homeostasis caused by the main psychoactive compound of cannabis, Δ 9-tetrahydrocannabinol (THC). We demonstrate that THC (10-40 µM) impairs placental endocannabinoid system by disrupting the endocannabinoid anandamide (AEA) levels and the expression of AEA synthetic and degrading enzymes N-arachidonoylphosphatidylethanolamine-specific phospholipase D (NAPE-PLD) and fatty acid amide hydrolase (FAAH), respectively. Although, no alterations in cannabinoid receptors CB1 and CB2 expression were observed. Thus, long-term local AEA levels are associated with a shift in the enzymatic profile to re-establish ECS homeostasis. In chronic cannabis users, high AEA levels in placenta may disturb the delicate balance of trophoblast cells turnover leading to alterations in normal placental development and foetal growth.

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Section: Introductionmentioning

confidence: 98%

Effects of cannabis tetrahydrocannabinol on endocannabinoid homeostasis in human placenta

et al. 2019

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“…Of note, the presence of a high concentration of AEA in follicular fluid is indicative of mature follicles [14,15], and significant differences of AEA and PEA in serum, and of OEA in follicular fluid, have been recorded between infertile and fertile women [16]. Furthermore, dysregulation of the ECS has been observed in polycystic ovary syndrome (PCOS) onset [17], as well as in altered human endometrial stromal cell decidualization [18].…”

Section: Introductionmentioning

confidence: 99%

Role of Major Endocannabinoid-Binding Receptors during Mouse Oocyte Maturation

Cecconi

Rossi

Oddi

et al. 2019

IJMS

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Endocannabinoids are key-players of female fertility and potential biomarkers of reproductive dysfunctions. Here, we investigated localization and expression of cannabinoid receptor type-1 and -2 (CB1R and CB2R), G-protein coupled receptor 55 (GPR55), and transient receptor potential vanilloid type 1 channel (TRPV1) in mouse oocytes collected at different stages of in vivo meiotic maturation (germinal vesicle, GV; metaphase I, MI; metaphase II, MII) through qPCR, confocal imaging, and western blot. Despite the significant decrease in CB1R, CB2R, and GPR55 mRNAs occurring from GV to MII, CB2R and GPR55 protein contents increased during the same period. At GV, only CB1R was localized in oolemma, but it completely disappeared at MI. TRPV1 was always undetectable. When oocytes were in vitro matured with CB1R and CB2R but not GPR55 antagonists, a significant delay of GV breakdown occurred, sustained by elevated intraoocyte cAMP concentration. Although CBRs antagonists did not affect polar body I emission or chromosome alignment, GPR55 antagonist impaired in ~75% of oocytes the formation of normal-sized MI and MII spindles. These findings open a new avenue to interrogate oocyte pathophysiology and offer potentially new targets for the therapy of reproductive alterations.

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“…There was evidence for a similar observation in humans. In this respect, AEA impairs cell proliferation and differentiation in the human endometrial stromal cell line and primary cultures of decidual fibroblasts from term pregnancy (25). There is further evidence that oxidative metabolites of AEA by Cox2 may compromise the normal decidual process (26,27).…”

Section: Discussionmentioning

confidence: 98%

Pregnancy success in mice requires appropriate cannabinoid receptor signaling for primary decidua formation

Dewar

Kim

et al. 2020

Preprint

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An early event after implantation is stromal cell transformation to decidual cells (decidualization) that support embryo development. In mice, this process begins at the antimesometrial (AM) pole with differentiation of stromal cells into epithelial-like cells (epithelioid cells) surrounding the implantation chamber. This is an avascular zone called the primary decidual zone (PDZ), and considered to function as a transient, size-dependent permeable barrier to protect the embryo from maternal circulating harmful agents, including immunoglobulins, immune cells, microorganisms and other noxious agents. This zone forms on day 5 afternoon and becomes fully established on day 6 with the loss of the crypt epithelium. The PDZ gradually degenerates with the appearance of the secondary decidual zone (SDZ) around the PDZ that peaks on day 8 in mice. Decidualization is critical for early pregnancy in mice and humans. We show that cannabinoid/endocannabinoid signaling influences decidualization in early pregnancy. Mice deficient in two major cannabinoid receptors, CB1 and CB2, show compromised PDZ. We found that angiogenic factors are dysregulated in Cnr1-/-Cnr2-/- mice with defective PDZs, resulting in the abnormal presence of blood vessels and macrophages in this zone; disruption of the PDZ compromises pregnancy outcomes. Using an in vitro decidualization model, we found that Cnr1 levels increase in mouse stromal cells and human uterine fibroblast (Huf) cells undergoing decidualization and that limiting CB1 signaling in these cell types suppresses decidualization in vitro. Since endothelial cells express Cnr2 and decidual cells express Cnr1, we hypothesize that angiogenic events driven by CB2 are integrated with CB1 in decidual cells, leading to proper PDZ formation, a critical step for pregnancy success.

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The endocannabinoid anandamide impairs in vitro decidualization of human cells

Cited by 35 publications

References 31 publications

Effects of cannabis tetrahydrocannabinol on endocannabinoid homeostasis in human placenta

Effects of cannabis tetrahydrocannabinol on endocannabinoid homeostasis in human placenta

Role of Major Endocannabinoid-Binding Receptors during Mouse Oocyte Maturation

Pregnancy success in mice requires appropriate cannabinoid receptor signaling for primary decidua formation

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