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The Endocannabinoid System in the Postimplantation Period: A Role during Decidualization and Placentation.
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PMID:  24228028     Owner:  NLM     Status:  PubMed-not-MEDLINE    
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Although the detrimental effects of cannabis consumption during gestation are known for years, the vast majority of studies established a link between cannabis consumption and foetal development. The complex maternal-foetal interrelationships within the placental bed are essential for normal pregnancy, and decidua definitively contributes to the success of this process. Nevertheless, the molecular signalling network that coordinates strategies for successful decidualization and placentation are not well understood. The discovery of the endocannabinoid system highlighted new signalling mediators in various physiological processes, including reproduction. It is known that endocannabinoids present regulatory functions during blastocyst development, oviductal transport, and implantation. In addition, all the endocannabinoid machinery was found to be expressed in decidual and placental tissues. Additionally, endocannabinoid's plasmatic levels were found to fluctuate during normal gestation and to induce decidual cell death and disturb normal placental development. Moreover, aberrant endocannabinoid signalling during the period of placental development has been associated with pregnancy disorders. It indicates the existence of a possible regulatory role for these molecules during decidualization and placentation processes, which are known to be particularly vulnerable. In this review, the influence of the endocannabinoid system in these critical processes is explored and discussed.
Authors:
B M Fonseca; G Correia-da-Silva; M Almada; M A Costa; N A Teixeira
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Publication Detail:
Type:  Journal Article; Review     Date:  2013-10-21
Journal Detail:
Title:  International journal of endocrinology     Volume:  2013     ISSN:  1687-8337     ISO Abbreviation:  Int J Endocrinol     Publication Date:  2013  
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Created Date:  2013-11-14     Completed Date:  2014-06-24     Revised Date:  2014-06-24    
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Nlm Unique ID:  101516376     Medline TA:  Int J Endocrinol     Country:  Egypt    
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Languages:  eng     Pagination:  510540     Citation Subset:  -    
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Journal ID (nlm-ta): Int J Endocrinol
Journal ID (iso-abbrev): Int J Endocrinol
Journal ID (publisher-id): IJE
ISSN: 1687-8337
ISSN: 1687-8345
Publisher: Hindawi Publishing Corporation
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Copyright © 2013 B. M. Fonseca et al.
open-access:
Received Day: 18 Month: 7 Year: 2013
Accepted Day: 4 Month: 9 Year: 2013
Print publication date: Year: 2013
Electronic publication date: Day: 21 Month: 10 Year: 2013
Volume: 2013E-location ID: 510540
PubMed Id: 24228028
ID: 3818851
DOI: 10.1155/2013/510540

The Endocannabinoid System in the Postimplantation Period: A Role during Decidualization and Placentation
B. M. Fonseca12
G. Correia-da-Silva12
M. Almada12
M. A. Costa12
N. A. Teixeira12*
1Biologia da Inflamação e Reprodução, Instituto de Biologia Molecular e Celular (IBMC), Rua do Campo Alegre No. 823, 4150-180 Porto, Portugal
2Laboratório de Bioquímica, Departamento Ciências Biológicas, Faculdade de Farmácia da Universidade do Porto, Ciências Biológicas Rua de Jorge Viterbo Ferreira No. 228, 4050-313 Porto, Portugal
Correspondence: *N. A. Teixeira: natercia@ff.up.pt
[other] Academic Editor: Haibin Wang

1. Cannabinoids: Historical Perspective

Cannabis sativa properties were known for centuries, though only in 1964 its main psychoactive component, Δ9-tetrahydrocannabinol (THC), was isolated and its chemical structure revealed. Due to its lipophilic nature, it was assumed that the psychotropic effects of THC resulted from interference with membrane fluidity, rather than binding to a specific receptor. However, by the mid 1980s, it was shown that cannabinoid activity was highly stereoselective, which led to the search for a specific receptor and its endogenous ligands [1, 2].

In late 1980s, cannabinoid receptors were discovered. The first cannabinoid receptor (CB1) was isolated from rat brain, [3] and, in 1993, a second receptor (CB2) was cloned from human promyelocytic leukaemia HL-60 cells [4].

Both cannabinoid receptors are G protein-coupled receptors (GPCRs), and their activation reduces adenylyl cyclase activity, leading to diminished cyclic adenosine monophosphate (cAMP) levels [5, 6]. Additionally, both receptors are coupled with intracellular signalling pathways related to activation of mitogen-activated protein kinases (MAPK). The CB1 is also coupled to ionic channels, inhibiting N- and P/Q-type voltage-gated calcium channels, activating A-type voltage-gated calcium channels, and inwardly rectifying potassium channels [57]. Furthermore, cannabinoids can modulate sphingolipid-metabolizing pathways by increasing intracellular levels of ceramide, an ubiquitous lipid second messenger [8].

On the other hand, as cannabinoids induced contractility of vascular smooth muscles independently of CB1 or CB2 receptors activation, it was suggested that other cannabinoid-like receptors may exist [9, 10]. Later, the orphan receptor GPR55 was suggested to be involved in non-CB1, non-CB2-mediated actions of cannabinoids [11]. Though with limited sequence homology with CB1 (13%) and CB2 (14%), GPR55 was suggested as a new cannabinoid receptor, the CB3 [12].


2. Endocannabinoid System

Besides THC, other molecules have been described to bind and activate cannabinoid receptors [13]. Some of these molecules were found to be produced by the organism and derived from arachidonic acid (AA), thus resulting in a new class of cannabinoids—the endocannabinoids (eCBs).

The first endocannabinoid, N-arachidonoylethanolamine, later called anandamide (AEA), was isolated in 1992 from pig brain by Raphael Mechoulam's group [14]. Three years later a second compound, the 2-arachidonoylglycerol (2-AG), was identified [15, 16].

Although cannabinoid receptors constitute the main targets of AEA, this molecule is capable of interacting with other molecular targets, such as the transient receptor potential vanilloid 1 (TRPV1) [17] and the peroxisome proliferator-activated receptors (PPARs) family [18, 19]. In opposition, 2-AG has higher affinity to CB1 and CB2 receptors than AEA, though it does not activate TRPV1.

Although AEA and 2-AG remain the best studied, other endogenous compounds may also bind cannabinoid receptors such as 2-arachidonoylglycerol ether (noladin ether, 2-AGE) [20], O-arachidonoylethanolamine (virodhamine) [21], N-arachidonoyl dopamine (NADA) [22], N-arachidonoyl glycine (NAGly) [23], and Cis-9,10-octadecanamide (oleamide or ODA) [24].

Like these molecules, other lipid mediators share endocannabinoid metabolic pathways. Although they are not able to bind to any of the cannabinoid receptors identified so far, these lipid messengers may influence endocannabinoid metabolism and function. These include the N-acylethanolamide family, particularly N-palmitoylethanolamide (PEA; C16:0), stearoylethanolamide (SEA, C18:0), and N-oleoylethanolamide (OEA; C18:1) [25].

Together with cannabinoid receptors and the endogenous compounds, the endocannabinoid system is also constituted by the putative membrane transporter and the enzymes responsible for the biosynthesis and degradation of endocannabinoids [26].

It is an accepted idea that endocannabinoids are released “on demand,” which means they are only produced when they are needed and on locals required. Based on the presence of intracellular AEA binding proteins, recent studies have been trying to prove the existence of AEA storage sites, believed to be adiposomes [27]. This hypothesis refutes the current conviction of an “on demand” production, so it must be carefully and extensively analysed.

The major endocannabinoids have different biosynthetic pathways, though both result from membrane precursors through enhanced intracellular Ca2+ concentrations. While AEA is synthesized from its precursor, the N-arachidonoyl-phosphatidylethanolamine (NAPE), by a specific phospholipase D (NAPE-PLD) [28], 2-AG is produced through a phospholipase C (PLC), producing 1,2-diacylglycerol (DAG), which may be, subsequently, converted to 2-AG by diacylglycerol lipase (DAGL) [29, 30].

Once synthesized, endocannabinoids are released to extracellular environment to target cannabinoid receptors, located in cell membranes, though AEA may also act on intracellular sites, such as TRPV1 receptor and T-type Ca2+ channels [31, 32]. Endocannabinoids appear to be inactivated through a two-step process involving the transport across the membrane, followed by two specific hydrolytic systems. Anandamide is primarily degraded by FAAH through hydrolysis into arachidonic acid and ethanolamine [33, 34]. Although FAAH can also degrade 2-AG [35] into glycerol and arachidonic acid, the main enzyme responsible for the inactivation of this compound is monoacyl glycerol lipase (MAGL) [36]. As AEA and 2-AG present structural similarities with polyunsaturated fatty acids, they can also serve as substrate for the inducible cyclooxygenase-2 (COX-2) and various lipoxygenases (LOXs) [37].

The current evidence indicates endocannabinoids as relevant modulators of several physiological functions not only in the central and autonomic nervous system but also in immune system, endocrine network, gastrointestinal tract, and in reproductive system [38].

During the last decade, the role of endocannabinoid system network in female reproduction has attracted major attention. Various evidences indicate a role for endocannabinoid elements during the preimplantation period. Endocannabinoids and both cannabinoid receptors have been described from the earliest stages of embryonic development to be involved in the regulation of blastocyst maturation, oviductal transport, implantation, and pregnancy maintenance. CB1 receptor is expressed in the embryo, in much higher levels than those in the brain [39]. Consistently, AEA was also found in much higher levels in mice nonpregnant uterus than in brain, which together with the changing levels of AEA with pregnancy status was indicative of a possible role for this lipid in early pregnancy events [40].

Endocannabinoid levels contribute to create the appropriate environment conducive to preimplantation embryo transport through the oviduct [41]. In fact, there is a regional regulation with higher expression of FAAH and NAPE-PLD in the ampulla and isthmus, respectively. This differential expression creates the appropriate AEA levels during oviductal transport.

A similar phenomenon is observed in mice uterus during implantation where expression of AEA-metabolizing enzymes in mouse uterus is critical to define their concentration in implantation sites and consequently in the implantation outcome. In fact, just before embryo implantation, AEA declines to barely detectable levels at the site of implantation, and this change is believed to contribute to the receptive uterine state [42]. AEA can also induce differential signals in blastocyst differentiation and outgrowth. At low levels, cultured blastocysts exhibited accelerated trophoblast differentiation and outgrowth, while higher levels induce opposite effects [43, 44]. Studies regarding the underlying mechanism of these biphasic effects revealed that stimulatory and inhibitory effects on blastocyst function and implantation depend on different signal transduction pathways. While AEA at low doses activates ERK signalling pathway, at high concentrations it inhibits Ca2+ influx. Both effects occur through CB1 receptor [44]. The AEA-biphasic effects reveal AEA as a potential “cannabinoid sensor” mechanism, influencing crucial steps during early pregnancy. Nowadays, it is well accepted that the embryo is a target for natural and endogenous cannabinoids, raising the significance of cannabinoid signalling in female fertility.

Whilst endocannabinoid signalling is clearly critical in early pregnancy events, its effects during decidualization and placentation period and implications in pregnancy outcome remain largely undefined.


3. Endocannabinoid System during Decidualization

Essential changes must occur in human endometrium to allow the establishment of pregnancy. These changes occur in the uterine endometrial stromal cells, which undergo a characteristic decidual cell reaction. Decidualization prepares the uterus for the trophoblast invasion that occurs during pregnancy.

In human, decidualization is present in normal menstrual cycle during the late secretory phase [45], whereas in rodents decidualization is only a blastocyst-dependent process in normal pregnancy [46]. At the site of blastocyst attachment, the endometrial stromal cells undergo decidual reaction, in which stromal cells proliferate and differentiate into decidual cells [47]. Morphologically, this process involves the differentiation of elongated fibroblast-like cells into enlarged polygonal epithelial-like decidual cells. Human decidual cells produce specific molecules such as inflammatory mediators like IL-1, IL-6, IL-8, and TNF-α [48], various regulatory factors including relaxin, renin, prolactin (PRL), and insulin-like growth factor binding protein-1 (IGFBP-1), [45, 49] and specific extracellular matrix proteins, such as laminin, type IV collagen, and fibronectin [50].

Anomalies on decidual process predispose to pregnancy complications, including miscarriage, preeclampsia, foetal growth restriction, and preterm labour.

The rat, just like human, exhibits a highly invasive type of placental development with subsequent remodelling of the uterine tissues, being a suitable model for studying the mechanisms of decidualization [46].

Studies in various mammals, including rats and humans, indicate that endocannabinoid system elements are present in decidua, which suggests its involvement in decidua establishment and/or remodelling (Figure 1) [5155].

Although limited data are available concerning human decidual tissue, Cb1 mRNA levels were detected in decidua from women with viable pregnancies [5658], as well as immunoreactivity for CB1, CB2, NAPE-PLD, and FAAH proteins [55]. During the follicular phase of menstrual cycle, AEA plasmatic levels were significantly higher than those in the luteal phase [59], suggesting that steroid hormones may also be involved in the regulation of AEA levels in human pregnancy as previously observed during early pregnancy in mice [60]. Together, these data point to a full functional endocannabinoid system naturally occurring in human decidual tissue during pregnancy. Currently, there are no studies considering the expression of 2-AG metabolic enzymes or 2-AG levels during human pregnancy.

In rodents, the stimulus for decidualization is not spontaneous, being the blastocyst crucial for this process. Detectable levels of proteins and respective mRNAs for metabolic enzymes (Faah, Nape-pld, Cox-2, Magl, and Daglα) and cannabinoid receptors (Cb1, Cb2, Gpr55, and Trpv1) in rat decidua throughout pregnancy [5154] were found. Among these, CB1 was markedly upregulated during midpregnancy, which corresponds in rodents to the maximum decidua development with subsequent regression to allow placental establishment [51].

Additionally, it was observed that FAAH, but not NAPE-PLD activity, varies significantly throughout pregnancy in rat maternal tissues. In fact, there is an increase in FAAH activity once decidua is fully developed, suggesting that a tight regulation of AEA levels is required during maternal tissues remodelling and supports a successful pregnancy (unpublished data).

The major endocannabinoids, AEA and 2-AG, and the endocannabinoid-like compounds, OEA and PEA, are detected in rat plasma and decidua during the postimplantation period [52, 53]. Contrary to AEA, in which plasmatic levels were increased on day 10, the other analysed compounds (2-AG, OEA, and PEA) remained relatively unchanged during the postimplantation period [52, 53]. However, the tissue levels for all the studied EC fluctuate according to the period of pregnancy. Collectively, the tissue levels indicate that all the studied compounds may be required during normal pregnancy. However, the levels of these molecules in plasma do not reflect the concentrations in uterine tissues, suggesting that they are tissues regulated [52, 53].

Unlike AEA and 2-AG, OEA and PEA are not able to activate CB1 and/or CB2 receptors or modulate cell survival and death [61, 62]. However, they may potentiate endocannabinoid biological actions through interference with their degradation, a so-called “entourage” effect, thereby leading to an enhancement of EC effects [63, 64]. In that way, their levels also need to be tightly regulated otherwise, they could exacerbate AEA actions and consequently impair normal pregnancy.

Besides a full endocannabinoid system present in decidual cells, a functional effect occurring during decidualization as result of CB1 activation was observed. Kesser et al. evidenced that WIN, a synthetic cannabinoid, inhibits the induction of human decidual cell differentiation, by decreasing mRNA levels of various decidualization-specific markers like prolactin, laminin, and IGFBP-1 [56]. Indeed, WIN-exposed cells showed a marked reduction in intracellular cAMP levels causing important changes in the morphology of decidual fibroblasts with DNA fragmentation. All these effects were reversed by the CB1 antagonist indicating that activation of CB1 inhibits human decidualization and stimulates apoptosis by a cAMP-dependent mechanism [56].

During the past few years, endocannabinoid effects have been extensively studied in several cell types, and, particularly for AEA, a proapoptotic effect has been demonstrated in endothelial cells [65], human neuroblastoma CHP100, and lymphoma U937 cells [66]. However, contrary effects have also been observed, like protecting cells from apoptosis [67] or stimulating proliferation of cancer cells [68].

Concerning decidual cells, AEA and 2-AG were described as proapoptotic compounds in primary rat decidual cells [52, 69]. While lower concentrations induced morphologic and molecular alterations, characteristic of an apoptotic cell death, higher concentrations resulted in a dramatic effect on cell viability and morphology and an increase in LDH release, probably due to a necrotic effect [52, 69]. This suggests a dual effect for endocannabinoids during fetoplacental development, which is dependent on endocannabinoid concentration.

On the other hand, the blockage of CB1 receptor, but not CB2 or TRPV1, was able to reverse the reduction of cell viability and apoptotic features induced by the two main endocannabinoids. Also, the activation of CB1 results in ceramide synthesis de novo and p38 phosphorylation, followed by induction of mitochondrial stress and ROS production, leading to apoptosis (Figure 2) [70]. Moreover, methyl-β-cyclodextrin (MCD), a cholesterol membrane depletor, has no effects on AEA/2-AG-programmed cell death [52, 69]. However, it has been referred that MCD blocks AEA-induced apoptosis in glioma cells [71] and hepatocytes [72]. This may result from CB1 redistribution in result of lipid raft disruption, as shown for breast cancer cells [73]. Furthermore, pretreatment with MCD increased decidual cell viability and caused a considerable reduction in LDH release only in the case of high concentrations of AEA and 2-AG [52, 69]. Thus, it is reasonable to suggest that high levels of AEA/2-AG, due to their lipophilic nature, may exert direct effects on rat decidual cells due to greater access through cholesterol-rich lipid rafts or through a membrane transporter present in these cells. Once inside the cell, these molecules induce detrimental effects that result in high cell cytotoxicity. In that way, depletion of membrane cholesterol inhibits this process and consequently inhibits cytotoxic effects without affecting the CB1-mediated apoptosis observed with the lower concentrations.

This evidence clearly indicates that membrane lipid composition and integrity may affect endocannabinoid signalling and uptake as previously observed in hepatic stellate cells. In these cells, alterations of membrane structure and cholesterol content reversed the cytotoxic effect of AEA/2-AG induced via mitochondrial reactive species [74, 75]. Consistently, CB1 activation in trophoblast cells during implantation may trigger different signalling pathways dependent on AEA levels [44].

Consistently with all these observations, an association between endocannabinoid system and decidua-related pregnancy disorders was shown. Lower CB1 expression was observed in decidua and fallopian tubes of women with ectopic pregnancy [76]. Additionally, AEA, OEA, and PEA plasmatic levels were all found to be significantly higher, whereas FAAH activity, but not NAPE-PLD activity, was significantly reduced in ectopic pregnancy [77]. These data suggest that aberrant endocannabinoid signalling in human decidua may result in ectopic pregnancy. Moreover, it points to a potential association between CB1 gene polymorphism and ectopic pregnancy.

Furthermore, AEA induces an increase in nitric oxide (NO) synthesis on decidua, which may implicate endocannabinoids in pathological reproductive events involving infection. These effects were abrogated by either co-incubation with CB1 or CB2 antagonists which suggests that both receptors could be mediating this effect [78].

Interestingly, it was observed that ECS regulates migration of endometrial stromal cell. More precisely, the synthetic cannabinoid methanandamide enhanced endometrial stromal cells migration via CB1, through the activation of PI3K/Akt and ERK1/2 pathways [79]. On the other hand, these observations were accompanied by cytoskeleton reorganization and increased electrical signal generated by K+ channels [79]. This suggests a potential role for endocannabinoids in some pathologic conditions characterized by enhanced endometrial cell invasiveness.

Decidualization process definitively contributes to the complex maternal-fetal relationships within placental bed crucial for normal pregnancy. Taken together, there is now sufficient evidence implicating endocannabinoid elements in decidualization process. On the other hand, a disruption in endocannabinoid levels may interfere with decidual tissue remodelling and consequently with trophoblast differentiation/proliferation or invasion, ultimately impairing placental function.

The significance of COX-2 and prostaglandins for the initiation and maintenance of decidualization is well established. COX-2 is restricted to implantation sites in most species, and targeted disruption of COX-2 in mice results in multiple reproductive impairments including decidualization [80].

FAAH is responsible for the metabolism of AEA to arachidonic acid, which provides a source for prostaglandins production. Anandamide is also a direct substrate to COX-2 oxidative metabolism eventually producing prostaglandin-ethanolamides (PG-EAs).

Some studies have recently shown that AEA is capable of modulating the production of prostaglandins. Consequently, induction of COX-2 expression may represent an underlying mechanism by which PGs may mediate eCB-dependent effects or vice versa [8183]. In the amnion, AEA caused a significant increase in PGE2 through CB1 [81, 84]. Similarly, it was described that AEA exerts opposite effects on PGE2 and F2α in mice uterine explants [84]. Moreover, COX-2 derivatives mediate anandamide-inhibitory effect on nitric oxide synthase activity in the receptive uterus [85, 86].

Low FAAH activity and increased AEA levels are apparent in peripheral lymphocytes in women with recurrent miscarriage or poor implantation in women undergoing in vitro fertilization [87]. Furthermore, FAAH expression was absent in trophoblasts cells of women who miscarried [88]. Thus, when FAAH activity is absent or low, AEA goes through an oxidative metabolism primarily by COX-2 driving to prostamide production. The longer half-life of prostamides raises the possibility that they might act as mediators, and they are currently the target of studies to explore their potential pathophysiological effects. Endocannabinoid-induced effects were described to be mediated by prostamides in tumorigenic keratinocytes [89] and in other systems [9092].

A latent biochemical cross-talk between the endocannabinoid and eicosanoid network is manifest. Furthermore, it is possible that aberrant endocannabinoid signalling may overwhelm eicosanoid expression compromising decidualization process and, in that way, fetoplacental development.


4. Endocannabinoid System during Placental Development

The placenta is a specialized pregnancy-specific structure that develops concurrently with the development of the embryo, being comprised of numerous cell types. Among them are specialized cells named trophoblasts, which are the earliest extraembryonic cells to differentiate from the mammalian embryo cells and surround the foetus throughout gestation.

Trophoblast cells are in direct contact with maternal tissues and play key roles in protecting the embryo/foetus from noxious substances, programming maternal support, and preventing maternal immune rejection. At the same time, they ensure appropriate bidirectional nutrient/waste flow required for growth and maturation of the embryo, enabling viviparous development. Thus, placentation is fundamental, creating the milieu, in which the embryo and foetus develop, assures a successful pregnancy, and even influences all the postnatal health and disease.

The balance between molecules synthesized by trophoblasts that promote invasion and inhibitors of this process, produced by decidua, controls the trophoblast invasiveness [9395]. In turn, imbalances on either side can lead to abnormal invasion, resulting in pregnancy problems. Although the underlying mechanisms of placentation remain largely unknown, endocannabinoid signalling may play an important role in this process (Figure 1).

Supported on experimental models indicating the deleterious action of cannabinoids in early pregnancy, some clinical studies about the effects of endocannabinoids on placentation have been published. Human first trimester placental tissues express FAAH and CB1, indicating human placenta as a target for cannabinoid action and metabolism [96, 97]. The higher levels of FAAH were observed in villous cytotrophoblasts and syncytiotrophoblasts, which correspond to the placental layers closest to the maternal blood [97], indicating that FAAH expression would be essential in the placenta during early pregnancy to protect the foetus from detrimental high levels of maternal AEA.

Some studies have addressed the association between FAAH expression and recurrent miscarriage. One study observed that invasive trophoblasts and decidual cells expressed significantly more FAAH in placenta from women with recurrent miscarriage than in those of normal pregnancies [58]. This indicates an inadequate control of the endocannabinoid system in the uterus of women who experience recurrent miscarriages. However, a contradictory result has been observed with lower FAAH and high CB1 expression in placental samples of spontaneous miscarriage as compared to normal pregnancy [88]. Moreover, this study also revealed nape-pld transcripts, providing evidence for a potential endogenous synthesis of AEA by first trimester human placenta [88].

More recently, contrary to FAAH, NAPE-PLD expression was shown to be significantly higher in preeclamptic than in normal placentas, though no differences were observed in CB1 expression [98]. It was also hypothesized that AEA has an important implication in the normal function of placental tissues by modulating nitric oxide synthase (NOS) activity. In fact, it was observed that AEA modulates rat NO placental levels by two independent pathways: by stimulating NO synthesis via TRPV1 or diminishing the NOS activity via cannabinoid receptors, which depends on the production of cyclooxygenase-2 derivatives [85, 99]. Since placental villous from women with preeclampsia presented amplified NOS activity, increased AEA levels may be due to higher NAPE-PLD expression [98].

Also, in rodents a fully endocannabinoid system in placenta was described. The levels of both major endocannabinoids in the placenta gradually increased reaching their maximum level by the end of pregnancy. This increase was accompanied by higher expression of respective synthesizing enzymes, whereas the hydrolysing enzymes remained unchanged in placenta throughout pregnancy [100]. It suggests that, since expression of hydrolysing enzymes was unaffected, the high levels of both endocannabinoids are, therefore, regulated by the synthesizing enzymes. Additionally, FAAH activity was maintained constant during placentation, whereas NAPE-PLD activity increased significantly by the end of pregnancy to support the increased AEA levels observed during labour (unpublished data).

Trophoblast cell differentiation is tightly regulated and endocannabinoid signalling appears to be relevant during such processes. It was found that ablation of CB1 receptor inhibited trophoblast cell proliferation, differentiation, and invasiveness resulting in defective placentation and fetal development. In parallel, an increase in fetal resorption rates in Cb1−/− females was observed, whereas trophoblast cell proliferation and differentiation were modestly affected in Faah−/− females with higher AEA levels [101, 102].

Furthermore, the exogenous cannabinoid THC and AEA have been shown to reduce BeWo trophoblast cell proliferation in vitro via CB2 receptor, suggesting that high AEA plasma levels may increase the risk of first trimester miscarriage [103, 104]. This may explain the detrimental effects of cannabis consumption, as THC crosses the placenta in a greater extent during early proliferative growth phase, and, unlike endocannabinoids, which are released on demand, THC persists for long periods within the body and thereby may impact normal gestation.


5. Concluding Remarks

Although the adverse effects of cannabinoids in pregnancy have been implicated for years, the exact signalling mechanisms involved remain fairly unclear. In fact, maternal marijuana use has been associated with foetal growth restrictions, spontaneous miscarriage, and cognitive deficits in infancy and adolescence.

With the discovery of cannabinoid receptors, endogenous ligands, and the enzymes involved in their metabolic pathways, a wealth of information is now available regarding the importance of cannabinoid signalling in reproduction. The AEA signalling mediated by CB1 is crucial to various female reproductive events that include embryo development, oviductal transport, and implantation. However, the involvement of endocannabinoids in the molecular dialogue governing both decidualization and placentation only recently started to be depicted.

There is now evidence that endocannabinoid system is fully expressed in maternal tissues and midgestational placentas, and the levels of its constituents fluctuate during normal gestation. Additionally, CB1 receptor stimulation is involved in the inhibition of human decidualization and in the natural remodelling process occurring during this period. Moreover, endocannabinoid signalling was shown to compromise placentation through disturbing trophoblast proliferation and differentiation. CB1 knock-out mice also revealed a deficient trophoblast invasion with consequences to placentation and successful pregnancy.

There is growing evidence supporting the involvement of the endocannabinoid system in decidualization and placentation along with a possible association between polymorphism genotypes of CB1 gene and ectopic pregnancy.

AEA or 2-AG, in higher levels, represents a deleterious factor during this complex process, and a similar mechanism for exocannabinoids may occur during cannabis consumption in pregnancy.

This observation raises the question as to whether and how potentially increased levels of these endocannabinoids would affect the process of decidualization. It is possible that sustained higher levels might generate an imbalance in CB1 stimulation that might be responsible for an exacerbated cell death of decidual cells impairing normal placentation. On the other hand and contrary to endocannabinoids, which are synthesized “on demand” and quickly hydrolysed, THC persists for longer periods in the human body and, in that way, can interfere with normal endocannabinoid balance, either through direct stimulation of CB1 receptor and/or indirectly interfering in endocannabinoid metabolism. Thus, exogenous cannabinoid exposure may overwhelm this local protection mechanism and interfere with stromal/decidual cells, trophoblast differentiation/proliferation, and interstitial/endovascular invasion impairing placental function, which may result in intrauterine retardation and low birth weight, some of the adverse effects of cannabis consumption during pregnancy.


Acknowledgment

B. M. Fonseca thanks Fundação para a Ciência e Tecnologia (FCT) for the Postdoctoral Grant (SFRH/BPD/72958/2010) and the Ph.D. Grants attributed to M. A. Costa (SFRH/BD/70721/2010) and M. Almada (SFRH/BD/81561/2011).


References
1. Howlett AC,Fleming RM. Cannabinoid inhibition of adenylate cyclase. Pharmacology of the response in neuroblastoma cell membraneMolecular PharmacologyYear: 19842635325382-s2.0-00217229836092901
2. Razdan RK. Structure-activity relationships in cannabinoidsPharmacological ReviewsYear: 1986382751492-s2.0-00228855923018800
3. Matsuda LA,Lolait SJ,Brownstein MJ,Young AC,Bonner TI. Structure of a cannabinoid receptor and functional expression of the cloned cDNANatureYear: 199034662845615642-s2.0-00253255352165569
4. Munro S,Thomas KL,Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoidsNatureYear: 1993365644161652-s2.0-00275153737689702
5. Bisogno T,Ligresti A,Di Marzo V. The endocannabinoid signalling system: biochemical aspectsPharmacology Biochemistry and BehaviorYear: 20058122242382-s2.0-20444460345
6. Păunescu H,Coman OA,Coman L,et al. Cannabinoid system and cyclooxygenases inhibitorsJournal of Medicine and LifeYear: 20114112021505570
7. Patsos HA,Greenhough A,Hicks DJ,et al. The endogenous cannabinoid, anandamide, induces COX-2-dependent cell death in apoptosis-resistant colon cancer cellsInternational Journal of OncologyYear: 20103711871932-s2.0-7795321152320514410
8. Velasco G,Galve-Roperh I,Sánchez C,Blázquez C,Haro A,Guzmán M. Cannabinoids and ceramide: two lipids acting hand-by-handLife SciencesYear: 20057714172317312-s2.0-2304451718415958274
9. Begg M,Pacher P,Bátkai S,et al. Evidence for novel cannabinoid receptorsPharmacology & TherapeuticsYear: 2005106213314515866316
10. Járai Z,Wagner JA,Varga K,et al. Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptorsProceedings of the National Academy of Sciences of the United States of AmericaYear: 1999962414136141412-s2.0-003884560410570211
11. Baker D,Pryce G,Davies WL,Hiley CR. In silico patent searching reveals a new cannabinoid receptorTrends in Pharmacological SciencesYear: 2006271142-s2.0-3034447697216318877
12. Sawzdargo M,Nguyen T,Lee DK,et al. Identification and cloning of three novel human G protein-coupled receptor genes GPR52, ΨGPR53 and GPR55: GPR55 is extensively expressed in human brainMolecular Brain ResearchYear: 19996421931982-s2.0-00335246449931487
13. Pertwee RG. Pharmacological actions of cannabinoidsHandbook of Experimental PharmacologyYear: 2005168152-s2.0-3114444970516596770
14. Devane WA,Hanus L,Breuer A,et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptorScienceYear: 19922585090194619492-s2.0-00270786851470919
15. Mechoulam R,Ben-Shabat S,Hanuš L,et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptorsBiochemical PharmacologyYear: 199550183902-s2.0-00290120147605349
16. Sugiura T,Kondo S,Sukagawa A,et al. 2-arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brainBiochemical and Biophysical Research CommunicationsYear: 1995215189972-s2.0-00289705177575630
17. Zygmunt PM,Petersson J,Andersson DA,et al. Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamideNatureYear: 199940067434524572-s2.0-003361498410440374
18. O’Sullivan SE. Cannabinoids go nuclear: evidence for activation of peroxisome proliferator-activated receptorsBritish Journal of PharmacologyYear: 200715255765822-s2.0-3564900892617704824
19. O’Sullivan SE,Kendall DA. Cannabinoid activation of peroxisome proliferator-activated receptors: potential for modulation of inflammatory diseaseImmunobiologyYear: 201021586116162-s2.0-7795417511519833407
20. Hanus L,Abu-Lafi S,Fride E,et al. 2-Arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB1 receptorProceedings of the National Academy of Sciences of the United States of AmericaYear: 2001987366236652-s2.0-003595742511259648
21. Porter AC,Sauer J-M,Knierman MD,et al. Characterization of a novel endocannabinoid, virodhamine, with antagonist activity at the CB1 receptorJournal of Pharmacology and Experimental TherapeuticsYear: 20023013102010242-s2.0-003626082312023533
22. Huang SM,Bisogno T,Trevisani M,et al. An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptorsProceedings of the National Academy of Sciences of the United States of AmericaYear: 20029912840084052-s2.0-003706241112060783
23. Huang SM,Bisogno T,Petros TJ,et al. Identification of a new class of molecules, the arachidonyl amino acids, and characterization of one member that inhibits painJournal of Biological ChemistryYear: 20012764642639426442-s2.0-003590069411518719
24. Leggett JD,Aspley S,Beckett SRG,D’Antona AM,Kendall DA,Kendall DA. Oleamide is a selective endogenous agonist of rat and human CB1 cannabinoid receptorsBritish Journal of PharmacologyYear: 200414122532622-s2.0-134234393614707029
25. Hansen HS. Palmitoylethanolamide and other anandamide congeners. Proposed role in the diseased brainExperimental NeurologyYear: 2010224148552-s2.0-7795372496520353771
26. Fonseca BM,Costa MA,Almada M,et al. Endogenous cannabinoids revisited: a biochemistry perspectiveProstaglandins & Other Lipid MediatorsYear: 2013102-103133023474290
27. Maccarrone M,Dainese E,Oddi S. Intracellular trafficking of anandamide: new concepts for signalingTrends in Biochemical SciencesYear: 201035116016082-s2.0-7804923226720570522
28. Okamoto Y,Morishita J,Tsuboi K,Tonai T,Ueda N. Molecular characterization of a phospholipase D generating anandamide and its congenersJournal of Biological ChemistryYear: 20042797529853052-s2.0-124229448014634025
29. Prescott SM,Majerus PW. Characterization of 1,2-diacylglycerol hydrolysis in human platelets. Demonstration of an arachidonoyl-monoacylglycerol intermediateJournal of Biological ChemistryYear: 198325827647692-s2.0-00206597656822511
30. Sugiura T,Kondo S,Sukagawa A,et al. 2-arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brainBiochemical and Biophysical Research CommunicationsYear: 1995215189972-s2.0-00289705177575630
31. Zygmunt PM,Petersson J,Andersson DA,et al. Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamideNatureYear: 199940067434524572-s2.0-003361498410440374
32. Chemin J,Monteil A,Perez-Reyes E,Nargeot J,Lory P. Direct inhibition of T-type calcium channels by the endogenous cannabinoid anandamideEMBO JournalYear: 20022024703370402-s2.0-003712661811742980
33. Deutsch DG,Chin SA. Enzymatic synthesis and degradation of anandamide, a cannabinoid receptor agonistBiochemical PharmacologyYear: 19934657917962-s2.0-00271803948373432
34. Cravatt BF,Giang DK,Mayfield SP,Boger DL,Lerner RA,Gilula NB. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amidesNatureYear: 1996384660483872-s2.0-00299048388900284
35. Goparaju SK,Ueda N,Yamaguchi H,Yamamoto S. Anandamide amidohydrolase reacting with 2-arachidonoylglycerol, another cannabinoid receptor ligandFEBS LettersYear: 1998422169732-s2.0-00325593699475172
36. Dinh TP,Freund TF,Piomelli D. A role for monoglyceride lipase in 2-arachidonoylglycerol inactivationChemistry and Physics of LipidsYear: 20021211-21491582-s2.0-003720708812505697
37. Fowler CJ. The contribution of cyclooxygenase-2 to endocannabinoid metabolism and actionBritish Journal of PharmacologyYear: 200715255946012-s2.0-3564901149517618306
38. Smita K,Sushil Kumar V,Premendran JS. Anandamide: an updateFundamental and Clinical PharmacologyYear: 2007211182-s2.0-3384618547217227440
39. Das SK,Paria BC,Chakraborty I,Dey SK. Cannabinoid ligand-receptor signaling in the mouse uterusProceedings of the National Academy of Sciences of the United States of AmericaYear: 19959210433243362-s2.0-00290744897753807
40. Schmid PC,Paria BC,Krebsbach RJ,Schmid HHO,Dey SK. Changes in anandamide levels in mouse uterus are associated with uterine receptivity for embryo implantationProceedings of the National Academy of Sciences of the United States of AmericaYear: 1997948418841922-s2.0-00309378299108127
41. Wang H,Guo Y,Wang D,et al. Aberrant cannabinoid signaling impairs oviductal transport of embryosNature MedicineYear: 20041010107410802-s2.0-7044227445
42. Schmid PC,Paria BC,Krebsbach RJ,Schmid HHO,Dey SK. Changes in anandamide levels in mouse uterus are associated with uterine receptivity for embryo implantationProceedings of the National Academy of Sciences of the United States of AmericaYear: 1997948418841922-s2.0-00309378299108127
43. Wang J,Paria BC,Dey SK,Armant DR. Stage-specific excitation of cannabinoid receptor exhibits differential effects on mouse embryonic developmentBiology of ReproductionYear: 19996048398442-s2.0-003303180510084956
44. Wang H,Matsumoto H,Guo Y,Paria BC,Roberts RL,Dey SK. Differential G protein-coupled cannabinoid receptor signaling by anandamide directs blastocyst activation for implantationProceedings of the National Academy of Sciences of the United States of AmericaYear: 20031002514914149192-s2.0-034473667614645706
45. Salamonsen LA,Dimitriadis E,Jones RL,Nie G. Complex regulation of decidualization: a role for cytokines and proteases—a reviewPlacentaYear: 200324S76S852-s2.0-014161499812842418
46. Fonseca BM,Correia-da-Silva G,Teixeira NA. The rat as an animal model for fetoplacental development: a reappraisal of the post-implantation periodReproductive BiologyYear: 20121229711822850465
47. Kearns M,Lala PK. Life history of decidual cells: a reviewAmerican Journal of Reproductive ImmunologyYear: 19833278822-s2.0-00206255906344664
48. Casey ML,MacDonald PC. Biomolecular processes in the initiation of parturition: decidual activationClinical Obstetrics and GynecologyYear: 19883135335522-s2.0-00237875063066543
49. Brosens JJ,Pijnenborg R,Brosens IA. The myometrial junctional zone spiral arteries in normal and abnormal pregnanciesAmerican Journal of Obstetrics and GynecologyYear: 20021875141614232-s2.0-003685408812439541
50. King A. Uterine leukocytes and decidualizationHuman Reproduction UpdateYear: 20006128362-s2.0-003395388410711827
51. Fonseca BM,Correia-da-Silva G,Taylor AH,Konje JC,Bell SC,Teixeira NA. Spatio-temporal expression patterns of anandamide-binding receptors in rat implantation sites: evidence for a role of the endocannabinoid system during the period of placental developmentReproductive Biology and EndocrinologyYear: 20097, article 1212-s2.0-71149083322
52. Fonseca BM,Correia-da-Silva G,Taylor AH,et al. The endocannabinoid 2-arachidonoylglycerol (2-AG) and metabolizing enzymes during rat fetoplacental development: a role in uterine remodellingInternational Journal of Biochemistry and Cell BiologyYear: 20104211188418922-s2.0-7795727050220727980
53. Fonseca BM,Correia-da-Silva G,Taylor AH,et al. N-acylethanolamine levels and expression of their metabolizing enzymes during pregnancyEndocrinologyYear: 20101518396539742-s2.0-7795492726420534733
54. Fonseca BM,Teixeira NA,Almada M,Taylor AH,Konje JC,Correia-Da-Silva G. Modulation of the novel cannabinoid receptor—GPR55—during rat fetoplacental developmentPlacentaYear: 20113264624692-s2.0-7995608857121497900
55. Taylor AH,Finney M,Lam PMW,Konje JC. Modulation of the endocannabinoid system in viable and non-viable first trimester pregnancies by pregnancy-related hormonesReproductive Biology and EndocrinologyYear: 20119, article 1522-s2.0-82255160646
56. Kesser CA,Moghadam KK,Schroeder JK,Buckley AR,Brar AK,Handwerger S. Cannabinoid receptor I activation markedly inhibits human decidualizationMolecular and Cellular EndocrinologyYear: 200522965742-s2.0-6054908448115607530
57. Horne AW,Phillips JA III,Kane N,et al. CB1 expression is attenuated in Fallopian tube and decidua of women with ectopic pregnancyPLoS ONEYear: 20083122-s2.0-58149089606e3969
58. Chamley LW,Bhalla A,Stone PR,et al. Nuclear localisation of the endocannabinoid metabolizing enzyme fatty acid amide hydrolase (FAAH) in invasive trophoblasts and an association with recurrent miscarriagePlacentaYear: 200829119709752-s2.0-5484944264918805581
59. Habayeb OMH,Taylor AH,Evans MD,et al. Plasma levels of the endocannabinoid anandamide in women—a potential role in pregnancy maintenance and labor?Journal of Clinical Endocrinology and MetabolismYear: 20048911548254872-s2.0-874429737715531501
60. Guo Y,Wang H,Okamoto Y,et al. N-acylphosphatidylethanolamine-hydrolyzing phospholipase D is an important determinant of uterine anandamide levels during implantationJournal of Biological ChemistryYear: 20052802523429234322-s2.0-2124446521115890658
61. Godlewski G,Offertáler L,Wagner JA,Kunos G. Receptors for acylethanolamides-GPR55 and GPR119Prostaglandins & Other Lipid MediatorsYear: 2009893-410511119615459
62. De Petrocellis L,Melck D,Bisogno T,Di Marzo V. Endocannabinoids and fatty acid amides in cancer, inflammation and related disordersChemistry and Physics of LipidsYear: 20001081-21912092-s2.0-003366592211106791
63. Di Marzo V,Melck D,Orlando P,et al. Palmitoylethanolamide inhibits the expression of fatty acid amide hydrolase and enhances the anti-proliferative effect of anandamide in human breast cancer cellsBiochemical JournalYear: 200135812492552-s2.0-003588154211485574
64. Ho W-SV,Barrett DA,Randall MD. ’Entourage’ effects of N-palmitoylethanolamide and N-oleoylethanolamide on vasorelaxation to anandamide occur through TRPV1 receptorsBritish Journal of PharmacologyYear: 200815568378462-s2.0-5734908830418695637
65. Yamaji K,Sarker KP,Kawahara K,et al. Anandamide induces apoptosis in human endothelial cells: its regulation system and clinical implicationsThrombosis and HaemostasisYear: 20038958758842-s2.0-003768743412719786
66. Maccarrone M,Lorenzon T,Bari M,Melino G,Finazzi-Agro A. Anandamide induces apoptosis in human cells via vanilloid receptors. Evidence for a protective role of cannabinoid receptorsJournal of Biological ChemistryYear: 20002754131938319452-s2.0-003464476910913156
67. Galve-Roperh I,Aguado T,Rueda D,Velasco G,Guzmán M. Endocannabinoids: a new family of lipid mediators involved in the regulation of neural cell developmentCurrent Pharmaceutical DesignYear: 20061218231923252-s2.0-3374516460816787257
68. Hart S,Fischer OM,Ullrich A. Cannabinoids induce cancer cell proliferation via tumor necrosis factor α-converting enzyme (TACE/ADAM17)-mediated transactivation of the epidermal growth factor receptorCancer ResearchYear: 2004646194319502-s2.0-154251062415026328
69. Fonseca BM,Correia-da-Silva G,Teixeira NA. Anandamide-induced cell death: dual effects in primary rat decidual cell culturesPlacentaYear: 20093086866922-s2.0-6765097343619560819
70. Fonseca BM,Correia-da-Silva G,Teixeira NA. The endocannabinoid anandamide induces apoptosis of rat decidual cells through a mechanism involving ceramide synthesis and p38 MAPK activationApoptosisYear: 2013
71. Sarker KP,Maruyama I. Anandamide induces cell death independently of cannabinoid receptors or vanilloid receptor 1: possible involvement of lipid raftsCellular and Molecular Life SciencesYear: 2003606120012082-s2.0-003872373912861385
72. Biswas KK,Sarker KP,Abeyama K,et al. Membrane cholesterol but not putative receptors mediates anandamide-induced hepatocyte apoptosisHepatologyYear: 2003385116711772-s2.0-014224490314578855
73. Sarnataro D,Grimaldi C,Pisanti S,et al. Plasma membrane and lysosomal localization of CB1 cannabinoid receptor are dependent on lipid rafts and regulated by anandamide in human breast cancer cellsFEBS LettersYear: 200557928634363492-s2.0-2774456201216263116
74. Siegmund SV,Uchinami H,Osawa Y,Brenner DA,Schwabe RF. Anandamide induces necrosis in primary hepatic stellate cellsHepatologyYear: 2005415108510952-s2.0-1784440478315841466
75. Siegmund SV,Qian T,De Minicis S,et al. The endocannabinoid 2-arachidonoyl glycerol induces death of hepatic stellate cells via mitochondrial reactive oxygen speciesFASEB JournalYear: 20072111279828062-s2.0-3454849952017440119
76. Horne AW,Phillips JA III,Kane N,et al. CB1 expression is attenuated in Fallopian tube and decidua of women with ectopic pregnancyPLoS ONEYear: 20083122-s2.0-58149089606e3969
77. Gebeh AK,Willets JM,Bari M,et al. Elevated anandamide and related N-acylethanolamine levels occur in the peripheral blood of women with ectopic pregnancy and are mirrored by changes in peripheral fatty acid amide hydrolase activityThe Journal of Clinical Endocrinology & MetabolismYear: 20139831226123423372171
78. Vercelli CA,Aisemberg J,Billi S,Wolfson ML,Franchi AM. Endocannabinoid system and nitric oxide are involved in the deleterious effects of lipopolysaccharide on murine deciduaPlacentaYear: 20093075795842-s2.0-6734911242419428101
79. Gentilini D,Besana A,Vigano P,et al. Endocannabinoid system regulates migration of endometrial stromal cells via cannabinoid receptor 1 through the activation of PI3K and ERK1/2 pathwaysFertility and SterilityYear: 2010938258825932-s2.0-7795210875320303477
80. Lim H,Paria BC,Das SK,et al. Multiple female reproductive failures in cyclooxygenase 2-deficient miceCellYear: 19979121972082-s2.0-00307021229346237
81. Mitchell MD,Sato TA,Wang A,Keelan JA,Ponnampalam AP,Glass M. Cannabinoids stimulate prostaglandin production by human gestational tissues through a tissue- and CB1-receptor-specific mechanismAmerican Journal of Physiology—Endocrinology and MetabolismYear: 20082942E352E3562-s2.0-3894915111318042663
82. Kuc C,Jenkins A,van Dross RT. Arachidonoyl ethanolamide (AEA)-induced apoptosis is mediated by J-series prostaglandins and is enhanced by fatty acid amide hydrolase (FAAH) blockadeMolecular CarcinogenesisYear: 20125121391492-s2.0-8485524323521432910
83. Hinz B,Ramer R,Eichele K,Weinzierl U,Brune K. Up-regulation of cyclooxygenase-2 expression is involved in R(+)-methanandamide-induced apoptotic death of human neuroglioma cellsMolecular PharmacologyYear: 2004666164316512-s2.0-944422936715361550
84. Vercelli CA,Aisemberg J,Cella M,et al. Opposite effects of methanandamide on lipopolysaccharide-induced prostaglandin E2 and F2alpha synthesis in uterine explants from pregnant micePLoS ONEYear: 201277e39532
85. Sordelli MS,Beltrame JS,Cella M,Franchi AM,Ribeiro ML. Cyclooxygenase-2 prostaglandins mediate anandamide-inhibitory action on nitric oxide synthase activity in the receptive rat uterusEuropean Journal of PharmacologyYear: 20126851–31741792-s2.0-8486056261022554772
86. Maccarrone M,Valensise H,Bari M,Lazzarin N,Romanini C,Finazzi-Agrò A. Relation between decreased anandamide hydrolase concentrations in human lymphocytes and miscarriageThe LancetYear: 20003559212132613292-s2.0-0034655926
87. Maccarrone M,Bisogno T,Valensise H,et al. Low fatty acid amide hydrolase and high anandamide levels are associated with failure to achieve an ongoing pregnancy after IVF and embryo transferMolecular Human ReproductionYear: 2002821881952-s2.0-003617227611818522
88. Trabucco E,Acone G,Marenna A,et al. Endocannabinoid system in first trimester placenta: low FAAH and high CB1 expression characterize spontaneous miscarriagePlacentaYear: 20093065165222-s2.0-6564910123319419760
89. Van Dross RT. Metabolism of anandamide by COX-2 is necessary for endocannabinoid-induced cell death in tumorigenic keratinocytesMolecular CarcinogenesisYear: 20094887247322-s2.0-6884911901919148897
90. Gatta L,Piscitelli F,Giordano C,et al. Discovery of prostamide F2α and its role in inflammatory pain and dorsal horn nociceptive neuron hyperexcitabilityPLoS ONEYear: 2012722-s2.0-84857382479e31111
91. Correa F,Docagne F,Clemente D,Mestre L,Becker C,Guaza C. Anandamide inhibits IL-12p40 production by acting on the promoter repressor element GA-12: possible involvement of the COX-2 metabolite prostamide E2Biochemical JournalYear: 200840937617702-s2.0-3894914323817961121
92. Patsos HA,Hicks DJ,Dobson RRH,et al. The endogenous cannabinoid, anandamide, induces cell death in colorectal carcinoma cells: a possible role for cyclooxygenase 2GutYear: 20055412174117502-s2.0-2814443177116099783
93. Feinberg RF,Kao L-C,Haimowitz JE,et al. Plasminogen activator inhibitor types 1 and 2 in human trophoblasts. PAI-1 is an immunocytochemical marker of invading trophoblastsLaboratory InvestigationYear: 198961120262-s2.0-00243497122473276
94. Graham CH,Lala PK. Mechanism of control of trophoblast invasion in situJournal of Cellular PhysiologyYear: 199114822282342-s2.0-00258952691652588
95. Strickland S,Richards WG. Invasion of the trophoblastsCellYear: 19927133553572-s2.0-00264785641423599
96. Park B,Gibbons HM,Mitchell MD,Glass M. Identification of the CB1 cannabinoid receptor and fatty acid amide hydrolase (FAAH) in the human placentaPlacentaYear: 200324109909952-s2.0-094227656214580383
97. Helliwell RJ,Chamley LW,Blake-Palmer K,et al. Characterization of the endocannabinoid system in early human pregnancyThe Journal of Clinical Endocrinology & MetabolismYear: 200489105168517415472222
98. Aban C,Leguizamón GF,Cella M,et al. Differential expression of endocannabinoid system in normal and preeclamptic placentas: effects on nitric oxide synthesisPlacentaYear: 2013341677423122699
99. Cella M,Leguizamón GF,Sordelli MS,et al. Dual effect of anandamide on rat placenta nitric oxide synthesisPlacentaYear: 20082986997072-s2.0-4904910333118561998
100. Fonseca BM,Correia-da-Silva G,Taylor AH,et al. Characterisation of the endocannabinoid system in rat haemochorial placentaReproductive ToxicologyYear: 201234334735622613199
101. Xie H,Sun X,Piao Y,et al. Silencing or amplification of endocannabinoid signaling in blastocysts via CB1 compromises trophoblast cell migrationJournal of Biological ChemistryYear: 201228738322883229722833670
102. Sun X,Xie H,Yang J,Wang H,Bradshaw HB,Dey SK. Endocannabinoid signaling directs differentiation of trophoblast cell lineages and placentationProceedings of the National Academy of Sciences of the United States of AmericaYear: 20101073916887168922-s2.0-7804923694020837524
103. Khare M,Taylor AH,Konje JC,Bell SC. Δ9-Tetrahydrocannabinol inhibits cytotrophoblast cell proliferation and modulates gene transcriptionMolecular Human ReproductionYear: 20061253213332-s2.0-3374477906416597638
104. Habayeb OMH,Taylor AH,Bell SC,Taylor DJ,Konje JC. Expression of the endocannabinoid system in human first trimester placenta and its role in trophoblast proliferationEndocrinologyYear: 200814910505250602-s2.0-5324910345918599552

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