Cannabidiol Exposure During Rat Pregnancy Leads to Labyrinth-Specific Vascular Defects in the Placenta and Reduced Fetal Growth

Introduction: Cannabis use is increasing among pregnant people, and cannabidiol (CBD), a constituent of cannabis, is often perceived as ‘‘natural’’ and ‘‘safe’’ as it is non-intoxicating. In utero, cannabis exposure is associated with negative health outcomes, including fetal growth restriction (FGR). The placenta supplies oxygen and nutrients to the fetus, and alterations in placental development can lead to FGR. While there has been some investigation into the effects of D9-THC, there has been limited investigation into the impacts of in utero gestational CBD exposure on the placenta. Methods: This study used histological and transcriptomic analysis of embryonic day (E)19.5 rat placentas from vehicle and CBD (3 mg/kg intraperitoneal injection) exposed pregnancies (E6.5-18.5). Results: The study revealed that pups from CBD-exposed pregnancies were 10% smaller, with the placentae displaying a decreased fetal blood space perimeter-to-area ratio. The transcriptomic analysis supported compromised angiogenesis and blood vessel formation with downregulated biological processes, including tube morphogenesis, angiogenesis, blood vessel morphogenesis, blood vessel development and vasculature development. Further, the CBD-exposed placentas displayed changed expression of glucose transporters (decreased GLUT1 and GR expression and increased GLUT3 expression). Transcriptomic analysis further revealed upregulated biological processes associated with metabolism. Finally, histological and transcriptomic analysis revealed altered cell populations within the placenta, specifically to syncytiotrophoblast layer II and endothelial cells. Conclusion: Together these results suggest that the structural changes in CDB-exposed placentae, including the altered expression of nutrient transporters and the changes to the placental fetal vasculature, may underlie the reduced fetal growth. https://www.liebertpub.com/doi/10.1089/can.2023.016

Δ9-tetrahydrocannabinol exposure during rat pregnancy leads to symmetrical fetal growth restriction and labyrinth-specific vascular defects in the placenta.

1 in 5 women report cannabis use during pregnancy, with nausea cited as their primary motivation. Studies show that (-)-△9-tetrahydrocannabinol (Δ9-THC), the major psychoactive ingredient in cannabis, causes fetal growth restriction, though the mechanisms are not well understood. Given the critical role of the placenta to transfer oxygen and nutrients from mother, to the fetus, any compromise in the development of fetal-placental circulation significantly affects maternal-fetal exchange and thereby, fetal growth. The goal of this study was to examine, in rats, the impact of maternal Δ9-THC exposure on fetal development, neonatal outcomes, and placental development. Dams received a daily intraperitoneal injection (i.p.) of vehicle control or Δ9-THC (3 mg/kg) from embryonic (E)6.5 through 22. Dams were allowed to deliver normally to measure pregnancy and neonatal outcomes, with a subset sacrificed at E19.5 for placenta assessment via immunohistochemistry and qPCR. Gestational Δ9-THC exposure resulted in pups born with symmetrical fetal growth restriction, with catch up growth by post-natal day (PND)21. During pregnancy there were no changes to maternal food intake, maternal weight gain, litter size, or gestational length. E19.5 placentas from Δ9-THC-exposed pregnancies exhibited a phenotype characterized by increased labyrinth area, reduced Epcam expression (marker of labyrinth trophoblast progenitors), altered maternal blood space, decreased fetal capillary area and an increased recruitment of pericytes with greater collagen deposition, when compared to vehicle controls. Further, at E19.5 labyrinth trophoblast had reduced glucose transporter 1 (GLUT1) and glucocorticoid receptor (GR) expression in response to Δ9-THC exposure. In conclusion, maternal exposure to Δ9-THC effectively compromised fetal growth, which may be a result of the adversely affected labyrinth zone development. These findings implicate GLUT1 as a Δ9-THC target and provide a potential mechanism for the fetal growth restriction observed in women who use cannabis during pregnancy

Early patterning of the chorion leads to the trilaminar trophoblast cell structure in the placental labyrinth

The labyrinth of the rodent placenta contains villi that are the site of nutrient exchange between mother and fetus. They are covered by three trophoblast cell types that separate the maternal blood sinusoids from fetal capillaries - a single mononuclear cell that is a subtype of trophoblast giant cell (sinusoidal or S-TGC) with endocrine function and two multinucleated syncytiotrophoblast layers, each resulting from cell-cell fusion, that function in nutrient transport. The developmental origins of these cell types have not previously been elucidated. We report here the discovery of cell-layer-restricted genes in the mid-gestation labyrinth (E12.5-14.5) including Ctsq in S-TGCs (also Hand1-positive), Syna in syncytiotrophoblast layer I (SynT-1), and Gcm1, Cebpa and Synb in syncytiotrophoblast layer II (SynT-II). These genes were also expressed in distinct layers in the chorion as early as E8.5, prior to villous formation. Specifically, Hand1 was expressed in apical cells lining maternal blood spaces (Ctsq is not expressed until E12.5), Syna in a layer immediately below, and Gcm1, Cebpa and Synb in basal cells in contact with the allantois. Cebpa and Synb were co-expressed with Gcm1 and were reduced in Gcm1 mutants. By contrast, Hand1 and Syna expression was unaltered in Gcm1 mutants, suggesting that Gcm1-positive cells are not required for the induction of the other chorion layers. These data indicate thatthe three differentiated trophoblast cell types in the abyrinth arise from distinct and autonomous precursors in the chorion that are patterned before morphogenesis begins

RGS14 is a mitotic spindle protein essential from the first division of the mammalian zygote.

Heterotrimeric G protein alpha subunits, RGS proteins, and GoLoco motif proteins have been recently implicated in the control of mitotic spindle dynamics in C. elegans and D. melanogaster. Here we show that regulator of G protein signaling-14 (RGS14) is expressed by the mouse embryonic genome immediately prior to the first mitosis, where it colocalizes with the anastral mitotic apparatus of the mouse zygote. Loss of Rgs14 expression in the mouse zygote results in cytofragmentation and failure to progress to the 2-cell stage. RGS14 is found in all tissues and segregates to the nucleus in interphase and to the mitotic spindle and centrioles during mitosis. Alteration of RGS14 levels in exponentially proliferating cells leads to cell growth arrest. Our results indicate that RGS14 is one of the earliest essential product of the mammalian embryonic genome yet described and has a general role in mitosis

InterPro in 2019: improving coverage, classification and access to protein sequence annotations

The InterPro database (http://www.ebi.ac.uk/interpro/) classifies protein sequences into families and predicts the presence of functionally important domains and sites. Here, we report recent developments with InterPro (version 70.0) and its associated software, including an 18% growth in the size of the database in terms on new InterPro entries, updates to content, the inclusion of an additional entry type, refined modelling of discontinuous domains, and the development of a new programmatic interface and website. These developments extend and enrich the information provided by InterPro, and provide greater flexibility in terms of data access. We also show that InterPro's sequence coverage has kept pace with the growth of UniProtKB, and discuss how our evaluation of residue coverage may help guide future curation activities

Ablation Versus Amiodarone for Treatment of Persistent Atrial Fibrillation in Patients With Congestive Heart Failure and an Implanted Device: Results From the AATAC Multicenter Randomized Trial

Background - Whether catheter ablation (CA) is superior to amiodarone (AMIO) for the treatment of persistent atrial fibrillation (AF) in patients with heart failure is unknown. Methods and Results - This was an open-label, randomized, parallel-group, multicenter study. Patients with persistent AF, dual-chamber implantable cardioverter defibrillator or cardiac resynchronization therapy defibrillator, New York Heart Association II to III, and left ventricular ejection fraction <40% within the past 6 months were randomly assigned (1:1 ratio) to undergo CA for AF (group 1, n=102) or receive AMIO (group 2, n=101). Recurrence of AF was the primary end point. All-cause mortality and unplanned hospitalization were the secondary end points. Patients were followed up for a minimum of 24 months. At the end of follow-up, 71 (70%; 95% confidence interval, 60%-78%) patients in group 1 were recurrence free after an average of 1.4\uc2\ub10.6 procedures in comparison with 34 (34%; 95% confidence interval, 25%-44%) in group 2 (log-rank P<0.001). The success rate of CA in the different centers after a single procedure ranged from 29% to 61%. After adjusting for covariates in the multivariable model, AMIO therapy was found to be significantly more likely to fail (hazard ratio, 2.5; 95% confidence interval, 1.5-4.3; P<0.001) than CA. Over the 2-year follow-up, the unplanned hospitalization rate was (32 [31%] in group 1 and 58 [57%] in group 2; P<0.001), showing 45% relative risk reduction (relative risk, 0.55; 95% confidence interval, 0.39-0.76). A significantly lower mortality was observed in CA (8 [8%] versus AMIO (18 [18%]; P=0.037). Conclusions - This multicenter randomized study shows that CA of AF is superior to AMIO in achieving freedom from AF at long-term follow-up and reducing unplanned hospitalization and mortality in patients with heart failure and persistent AF