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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. Anandamide (AEA) is an endogenous ligand for the cannabinoid receptors CB1 and CB2. Similarly to PG, endocannabinoids are implicated in different aspects of reproduction, such as maintenance of pregnancy and parturition. Little is known about the involvement of endocannabinoids on the onset of labor in an infectious milieu. Here, using a mouse model of preterm labor induced by lipopolysaccharide (LPS), we explored changes on the expression of components of endocannabinoid system (ECS). We have also determined whether AEA and CB antagonists alter PG production that induces labor. We observed an increase in uterine N-acylphosphatidylethanolamine-specific phospholipase D expression (NAPE-PLD, the enzyme that synthesizes AEA) upon LPS treatment. Activity of catabolic enzyme fatty acid amide hydrolase (FAAH) did not change significantly. In addition, we also found that LPS modulated uterine cannabinoid receptors expression by downregulating Cb2 mRNA levels and upregulating CB1 protein expression. Furthermore, LPS and AEA induced PGF2a augmentation, and this was reversed by antagonizing CB1 receptor. Collectively, our results suggest that ECS may be involved in the mechanism by which infection causes preterm birth.
Laboratorio de Fisiopatología de la Preñez y el Parto, Centro de Estudios Farmacológicos y Botánicos, UBA-CONICET, Ciudad Autónoma de Buenos Aires CP, Argentina
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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. In animal models, environmental stimulation and enrichment are associated with enhanced well-being, cognitive function and stress resilience. Here, we studied whether the exposure of BALB/c mice to an enriched environment (EE) regulates crucial events during early gestation at the maternal–fetal interface. Pregnant BALB/c mice were exposed to the EE that combines non-invasive stimuli from the sensory pathway with voluntary physical activity. The pregnancy rate was evaluated. Implantation sites were investigated microscopically and macroscopically. Vascular adaptation parameters at the maternal–fetal interface were analyzed. We found that exposure to the EE prevented pregnancy loss between gestational days 7 and 15. Also, it increased the diameter of the uterine artery and decreased the wall:lumen ratio of the mesometrial decidual vessels, suggesting that EE exposure promotes vascular remodeling. Moreover, it increased nitric oxide synthase activity and inducible nitric oxide synthase expression, as well as prostaglandin F2a production and endoglin expression in the implantation sites. Exposure of pregnant females to the EE regulates uterine physiology, promoting vascular remodeling during early gestation. These adaptations might contribute to preventing embryo loss. Our results highlight the importance of the maternal environment for pregnancy success. The design of an ‘EE-like’ protocol for humans could be considered as a new non-pharmacologic strategy to prevent implantation failure and recurrent miscarriage.
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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. Conversely, toward the end of pregnancy, the cervix must be remodeled to increase flexibility and allow the delivery. This process is called cervical remodeling and dysregulation of the process plays a role in premature delivery. The endocannabinoidome plays an important role in several reproductive events; however, its function on cervical tissue throughout pregnancy is poorly understood. The goal of this study was to evaluate the presence and participation of the endocannabinoidome in lipopolysaccharide (LPS)-induced cervical changes. Therefore, we evaluated key components of the endocannabinoidome in cervical tissue from nonpregnant mice and pregnant mice with and without LPS treatment. Using mass spectrometric analysis, we found an increase in anandamide and 2-arachidonoylglycerol in the cervix of pregnant mice when compared to nonpregnant mice. We have also found a reduction in FAAH protein expression in these tissues. Furthermore, when treated with LPS, we observed a reduction in the cervical immunostaining with anti-CB1 and anti-CB2 antibodies. Likewise, using cervix explants from pregnant mice, we found that LPS significantly increased cervical metalloprotease activity and cyclooxygenase 2, which were subsequently modulated by cannabinoid receptor antagonists. Collectively, our findings suggest that an LPS-induced imbalance of cervix endocannabinoidome likely contributes to premature cervical remodeling, which is part of the key components that contribute to premature delivery.
