Endocannabinoid regulation in the cervix during pregnancy: insights into molecular mechanisms of premature labor.

In Brief: The cervix plays a crucial role not only in the maintenance of pregnancy but also during delivery, when it undergoes extensive changes. This study highlights the involvement of the endocannabinoidome in cervical remodeling, emphasizing its relevance in the shift from a nonpregnant to pregnant state and its potential contribution to preterm delivery in inflammatory contexts.

Abstract: During pregnancy, the main role of the cervix is to isolate the fetus from outside pathogens and maintain the relatively closed system of uterine gestation.

A physiological concentration of anandamide promotes the migration of human endometrial fibroblast and the interaction with endothelial cells invitro.

Introduction: The mechanisms that govern fibroblast behavior during the vascular adaptations of the uterus at early pregnancy remain unknown. Anandamide, an endocannabinoid, binds to cannabinoid receptors (CBs), and regulates gestation and angiogenesis. Its tone is regulated by fatty acid amide hydrolase (FAAH) within the uterus.

Maternal exposure to an enriched environment promotes uterine vascular remodeling and prevents embryo loss in mice.

Implantation-related events are crucial for pregnancy success. In particular, defects in vascular remodeling at the maternal-fetal interface are associated with spontaneous miscarriage and recurrent pregnancy loss. Physical activity and therapies oriented to reduce stress improve pregnancy outcomes.

Maternal obesity reverses the resistance to LPS-induced adverse pregnancy outcome and increases female offspring metabolic alterations in cannabinoid receptor 1 knockout mice.

Maternal overnutrition negatively impacts the offspring's health leading to an increased risk of developing chronic diseases or metabolic syndrome in adulthood. What we eat affects the endocannabinoid system (eCS) activity, which in turn modulates lipogenesis and fatty acids utilization in hepatic, muscle, and adipose tissues. This study aimed to evaluate the transgenerational effect of maternal obesity on cannabinoid receptor 1 knock-out (CB1 KO) animals in combination with a postnatal obesogenic diet on the development of metabolic disturbances on their offspring.

Maternal environmental enrichment modulates the immune response against an inflammatory challenge during gestation and protects the offspring.

The production of pro-inflammatory cytokines during inflammatory processes has been associated with preterm birth (PTB) and fetal injury in humans and mice. We previously demonstrated that exposition to an enriched environment (EE), defined as a noninvasive and biological significant stimulus of the sensory pathway combined with voluntary physical activity, prevented PTB and perinatal death induced by the systemic administration of bacterial lipopolysaccharide (LPS) in mice. This work aimed to analyze whether EE modulates the immune response to the inflammatory process induced by LPS in peripheral blood and the amniotic fluid (AF).

The enrichment of maternal environment prevents pre-term birth in a mice model.

Maternal lifestyle affects both mother health and pregnancy outcome in humans. Several studies have demonstrated that interventions oriented toward reducing stress and anxiety have positive effects on pregnancy complications such as preeclampsia, excessive gestational weight, gestational diabetes and preterm birth. In this work, we showed that the environmental enrichment (EE), defined as a noninvasive and biologically significant stimulus of the sensory pathway combined with voluntary physical activity, prevented preterm birth (PTB) rate by 40% in an inflammatory mouse model induced by the systemic administration of bacterial lipopolysaccharide (LPS).

Maternal obesogenic diet combined with postnatal exposure to high-fat diet induces metabolic alterations in offspring.

Maternal obesity has been shown to impact the offspring health during childhood and adult life. This study aimed to evaluate whether maternal obesity combined with postnatal exposure to an obesogenic diet could induce metabolic alterations in offspring. Female CD1 mice were fed a control diet (CD, 11.

Lysophosphatidic acid induces the crosstalk between the endovascular human trophoblast and endothelial cells in vitro.

Spiral artery remodeling at the maternal-fetal interface is crucial for successful pregnancy and requires the interaction between the first trimester trophoblast and the endothelial cells of the maternal vessels. However, the precise mechanism of this dialog has yet to be determined. The current study investigated whether lysophosphatidic acid (LPA) modulates trophoblast-endothelial crosstalk in vitro.

Shiga Toxin-Producing Infections during Pregnancy.

Gastrointestinal infection with Shiga toxin-producing (STEC) causes diarrhea, hemorrhagic colitis, and hemolytic uremic syndrome (HUS), characterized by hemolytic anemia, thrombocytopenia and acute renal failure. The main virulence factor of STEC is Shiga toxin (Stx), which is responsible for HUS development. STEC can produce Stx type 1 and/or 2 (Stx1, Stx2) and their variants, Stx2 being more frequently associated with severe cases of HUS.

Resveratrol protects from lipopolysaccharide-induced inflammation in the uterus and prevents experimental preterm birth.

Study Question: Is resveratrol able to prevent the lipopolysaccharide (LPS)-induced preterm labor in 15-day pregnant BALB/c mice?

Summary Answer: Resveratrol prevented the LPS-induced onset of preterm labor in 64% of the cases and showed anti-inflammatory and tocolytic effects by downregulating COX-2 and iNOS expression and NOS activity, and by changing the uterine prostaglandin and endocannabinoid profiling.

What Is Known Already: Genital tract infections by Gram-negative bacteria are a common complication in human pregnancy and have been shown to increase risk of preterm delivery. Bacterial LPS elicits a strong maternal inflammatory response that results in preterm delivery and fetal death in a murine model endotoxin-induced preterm labor.

Maternal administration of melatonin exerts short- and long-term neuroprotective effects on the offspring from lipopolysaccharide-treated mice.

Preterm birth is a major contributor to early and delayed physical and cognitive impairment. Epidemiological and experimental data indicate that maternal infections are a significant and preventable cause of preterm birth. Recently, melatonin has been suggested to exert neuroprotective effects in several models of brain injury.

Lysophosphatidic acid-triggered pathways promote the acquisition of trophoblast endovascular phenotype in vitro.

Successful implantation and placentation requires that extravillous cytotrophoblast acquires an endovascular phenotype and remodels uterine spiral arteries. Defects in this mechanism correlate with severe obstetric complications as implantation failure and preeclampsia. Lysophosphatidic acid (LPA) participates in embryo implantation and contributes to vascular physiology in different biological systems.

Evidence for CB2 receptor involvement in LPS-induced reduction of cAMP intracellular levels in uterine explants from pregnant mice: pathophysiological implications.

Study Question: What is the role of the endocannabinoid system (eCS) on the lipopolysaccharide (LPS) effects on uterine explants from 7-day pregnant mice in a murine model of endotoxin-induced miscarriage?

Summary Answer: We found evidence for cannabinoid receptor type2 (CB2) involvement in LPS-induced increased prostaglandin-F2α (PGF2α) synthesis and diminished cyclic adenosine monophosphate (cAMP) intracellular content in uterine explants from early pregnant mice.

What Is Known Already: Genital tract infections by Gram-negative bacteria are a common complication of human pregnancy that results in an increased risk of pregnancy loss. LPS, the main component of the Gram-negative bacterial wall, elicits a strong maternal inflammatory response that results in embryotoxicity and embryo resorption in a murine model endotoxin-induced early pregnancy loss.

Endogenous lysophosphatidic acid participates in vascularisation and decidualisation at the maternal-fetal interface in the rat.

Lysophosphatidic acid (LPA) affects several female reproductive functions through G-protein-coupled receptors. LPA contributes to embryo implantation via the lysophospholipid LPA receptor. In the present study we investigated the participation of endogenous LPA signalling through the LPA receptor in vascularisation and decidualisation, two crucial events at the maternal-fetal interface.

A role for the endocannabinoid system in premature luteal regression and progesterone withdrawal in lipopolysaccharide-induced early pregnancy loss model.

Study Question: What is the role of the endocannabinoid system (eCS) in the alterations of the endocrine system in a murine model of lipopolysaccharide (LPS)-induced miscarriage?

Summary Answer: In 7-days pregnant wild type, but not cannabinoid receptor type 1 knockout (CB1-KO) mice, LPS increased COX-2 expression and prostaglandin F (PGF) production in the uterus leading to lower expression of prolactin receptor in the ovary and a marked regression of corpora lutea (CL), suggesting that the eCS mediates the deleterious effects of LPS on reproductive events.

What Is Known Already: Appropriate systemic progesterone levels are critical for a successful pregnancy outcome. Precocious loss of luteal progesterone (P4) secretion leads to miscarriage in rodents.

Endocannabinoid system and pregnancy.

The endocannabinoid system (eCS), is a complex system, comprising the main endogenous ligands anandamide and 2-arachidonoyl glycerol, the cannabinoid receptors CB1 and CB2 and the biosynthetic and degrading enzymes. Cumulative evidence shows that the eCS plays an important role in reproduction, from egg fertilization to parturition. Therefore, alterations in this system, either by recreation/therapeutic use of cannabis or deregulation of the endogenous cannabinoids, might lead to adverse pregnancy outcomes, including retardation in embryo development, poor blastocyst implantation, inhibition of decidualization, miscarriage and compromised placentation.

Peripheral Blood Mononuclear Cells Infiltration Downregulates Decidual FAAH Activity in an LPS-Induced Embryo Resorption Model.

Maternal infections with gram-negative bacteria are associated with miscarriage and are one of the most common complications during pregnancy. Previous studies from our group have shown that lipopolysaccharide (LPS)-activated infiltrating peripheral blood mononuclear cells (PBMC) into decidual tissue plays an important role in the establishment of a local inflammatory process that results in embryo cytotoxicity and early embryo resorption. Moreover, we have also shown that an increased endocannabinoid tone mediates LPS-induced deleterious effects during early pregnancy loss.

Heparin exerts anti-apoptotic effects on uterine explants by targeting the endocannabinoid system.

Miscarriage caused by Gram-negative bacteria infecting the female genital tract is one of the most common complications of human pregnancy. Intraperitoneal administration of LPS to 7-days pregnant mice induces embryo resorption after 24 h. Here, we show that LPS induced apoptosis on uterine explants from 7-days pregnant mice and that CB1 receptor was involved in this effect.

Ethanol downregulates N-acyl phosphatidylethanolamine-phospholipase D expression in BV2 microglial cells via epigenetic mechanisms.

Excessive ethanol drinking has deleterious effects on the brain. However, the effects of alcohol on microglia, the main mediator of the brain's innate immune response remain poorly understood. On the other hand, the endocannabinoid system plays a fundamental role in regulating microglial reactivity and function.

Progesterone modulates the LPS-induced nitric oxide production by a progesterone-receptor independent mechanism.

Genital tract infections caused by Gram-negative bacteria induce miscarriage and are one of the most common complications of human pregnancy. LPS administration to 7-day pregnant mice induces embryo resorption after 24h, with nitric oxide playing a fundamental role in this process. We have previously shown that progesterone exerts protective effects on the embryo by modulating the inflammatory reaction triggered by LPS.

Role of the endocannabinoid system in the mechanisms involved in the LPS-induced preterm labor.

Prematurity is the leading cause of perinatal morbidity and mortality worldwide. There is a strong causal relationship between infection and preterm births. Intrauterine infection elicits an immune response involving the release of inflammatory mediators like cytokines and prostaglandins (PG) that trigger uterine contractions and parturition events.

Lipopolysaccharide-induced murine embryonic resorption involves changes in endocannabinoid profiling and alters progesterone secretion and inflammatory response by a CB1-mediated fashion.

Genital tract infections are a common complication of human pregnancy that can result in miscarriage. We have previously shown that a lipopolysaccharide (LPS) induces embryonic resorption in a murine model of inflammatory miscarriage. This is accompanied by a dramatic decrease in systemic progesterone levels associated with a robust pro-inflammatory response that results in embryo resorption.

Effects of Shiga toxin type 2 on maternal and fetal status in rats in the early stage of pregnancy.

Shiga toxin type 2 (Stx2), a toxin secreted by Shiga toxin-producing Escherichia coli (STEC), could be one of the causes of maternal and fetal morbimortality not yet investigated. In this study, we examined the effects of Stx2 in rats in the early stage of pregnancy. Sprague-Dawley pregnant rats were intraperitoneally (i.

Inflammation, infection and preterm birth.

Preterm birth is the leading cause of perinatal morbidity and mortality. Pathological processes that have been linked with preterm birth infection and / or intrauterine inflammation are most frequently found associated with their induction. Studies in animal models and human research showed prior infections to the induction of labor, the anteriority of infection over labor induction, and the existence of a subclinical latency phase between these two phenomena.

Melatonin prevents experimental preterm labor and increases offspring survival.

Preterm delivery is the leading cause of neonatal mortality and contributes to delayed physical and cognitive development in children. At present, there is no efficient therapy to prevent preterm labor. A large body of evidence suggests that intra-amniotic infections may be a significant and potentially preventable cause of preterm birth.