Placental development during early pregnancy: Effects of embryo origin on expression of chemokine ligand twelve (CXCL12)

Abstract Early pregnancy features complex signaling between fetal trophoblast cells and maternal endometrium directing major peri-implantation events including localized inflammation and remodeling to establish proper placental development. Proinflammatory mediators are important for conceptus attachment, but a more precise understanding of molecular pathways regulating this process is needed to understand how the endometrium becomes receptive to implantation. Both chemokine ligand 12 (CXCL12) and its receptor CXCR4 are expressed by fetal and maternal tissues. We identified this pair as a critical driver of placental angiogenesis, but their additional importance to inflammation and trophoblast cell survival, proliferation, and invasion imply a role in syncytia formation at the fetal–maternal microenvironment. We hypothesized that CXCL12 encourages both endometrial inflammation and conceptus attachment during implantation. We employed separate ovine studies to (1) characterize endometrial inflammation during early gestation in the ewe, and (2) establish functional implications of CXCL12 at the fetal–maternal interface through targeted intrauterine infusion of the CXCR4 inhibitor AMD3100. Endometrial tissues were evaluated for inflammatory mediators, intracellular signaling events, endometrial modifications, and trophoblast syncytialization using western blotting and immunohistochemistry. Endometrial tissue from ewes receiving CXCR4 inhibitor demonstrated dysregulated inflammation and reduced AKT and NFKB, paired with elevated autophagic activity compared to control. Immunohistochemical observation revealed an impairment in endometrial surface remodeling and diminished trophoblast syncytialization following localized CXCR4 inhibition. These data suggest CXCL12–CXCR4 regulates endometrial inflammation and remodeling for embryonic implantation, and provide insight regarding mechanisms that, when dysregulated, lead to pregnancy pathologies such as intrauterine growth restriction and preeclampsia.

Download Full-text

Cell-specific expression and signal transduction of C-C motif chemokine ligand 2 and atypical chemokine receptors in the porcine endometrium during early pregnancy

Developmental & Comparative Immunology ◽

10.1016/j.dci.2017.12.020 ◽

2018 ◽

Vol 81 ◽

pp. 312-323 ◽

Cited By ~ 22

Author(s):

Whasun Lim ◽

Hyocheol Bae ◽

Fuller W. Bazer ◽

Gwonhwa Song

Keyword(s):

Signal Transduction ◽

Early Pregnancy ◽

Chemokine Receptors ◽

Specific Expression ◽

Chemokine Ligand ◽

Chemokine Ligand 2

Download Full-text

Maternal Nutrition in Early Pregnancy Effects Placental Development

International Journal of Medicine and Public Health ◽

10.5530/ijmedph.2.2011.6 ◽

2011 ◽

Vol 1 (2) ◽

pp. 22-29

Author(s):

JJ Babu Geddam ◽

Radhakrishna KV ◽

Ramalaxmi BA ◽

Balakrishna N ◽

Qadri SSYH ◽

...

Keyword(s):

Early Pregnancy ◽

Maternal Nutrition ◽

Placental Development

Download Full-text

Placental development during early pregnancy in sheep: vascular growth and expression of angiogenic factors in maternal placenta

Reproduction ◽

10.1530/rep-09-0548 ◽

2010 ◽

Vol 140 (1) ◽

pp. 165-174 ◽

Cited By ~ 50

Author(s):

Anna T Grazul-Bilska ◽

Pawel P Borowicz ◽

Mary Lynn Johnson ◽

Megan A Minten ◽

Jerzy J Bilski ◽

...

Keyword(s):

Growth Factor ◽

Fetal Growth ◽

Early Pregnancy ◽

Vascular Development ◽

Hypoxia Inducible Factor ◽

Angiogenic Factors ◽

Placental Development ◽

Proliferating Cells ◽

Placental Angiogenesis ◽

Tissue Area

Placental vascular development (angiogenesis) is critical for placental function and thus for normal embryonic/fetal growth and development. Specific environmental factors or use of assisted reproductive techniques may result in poor placental angiogenesis, which may contribute to embryonic losses and/or fetal growth retardation. Uterine tissues were collected on days 14, 16, 18, 20, 22, 24, 26, 28, and 30 after mating and on day 10 after estrus (nonpregnant controls) to determine vascular development and expression of several factors involved in the regulation of angiogenesis in the endometrium. Compared with controls, several measurements of endometrial vascularity increased (P<0.001) including vascular labeling index (LI; proportion of proliferating cells), the tissue area occupied by capillaries, area per capillary (capillary size), total capillary circumference per unit of tissue area, and expression of factor VIII (marker of endothelial cells), but capillary number decreased (P<0.001). Compared with controls, mRNA for placental growth factor, vascular endothelial growth factor receptors, angiopoietins (ANGPT) 1 and 2, ANGPT receptorTEK, endothelial nitric oxide synthase, and hypoxia-inducible factor 1α increased (P<0.05) during early pregnancy. Vascular LI was positively correlated (P<0.05) with several measurements of vascularity and with mRNA expression of angiogenic factors. These data indicate that endometrial angiogenesis, manifested by increased vascularity and increased expression of several factors involved in the regulation of angiogenesis, is initiated very early in pregnancy. This more complete description of early placental angiogenesis may provide the foundation for determining whether placental vascular development is altered in compromised pregnancies.

Download Full-text

Placental Development and Early Pregnancy Pathology

The Global Library of Women s Medicine ◽

10.3843/glowm.10150 ◽

2009 ◽

Author(s):

Carolyn M. Salafia ◽

Edwina J. Popek

Keyword(s):

Early Pregnancy ◽

Placental Development

Download Full-text

Role for endocannabinoids in early pregnancy: recent advances and the effects of cannabis use

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00210.2020 ◽

2020 ◽

Vol 319 (3) ◽

pp. E557-E561 ◽

Cited By ~ 1

Author(s):

Henry C. Ezechukwu ◽

Cornelius A. Diya ◽

Nirajan Shrestha ◽

Deanne H. Hryciw

Keyword(s):

Early Pregnancy ◽

Pregnancy Outcomes ◽

Cannabinoid Receptors ◽

Negative Impact ◽

Receptor Expression ◽

Reproductive Age ◽

Placental Development ◽

Endometrial Stromal Cells ◽

Recent Advances ◽

Excessive Intake

The endocannabinoid system (ECS) is associated with several physiological processes, including reproduction. This system consists of the cannabinoid receptors, endocannabinoid ligands, and enzymes that metabolize and degrade these fatty acids. Recent evidence shows that cannabinoid receptors are expressed in cells of the reproductive system, including endometrial stromal cells, ovaries, and sperm cells. Emerging and recent research suggests that the ECS may play a significant role in reproduction. The endocannabinoid ligands anandamide and 2-arachidonoylglycerol are crucial for successful endometrium decidualization, placental development, and embryo implantation. Alteration in cannabinoid receptor expression or in endocannabinoid homeostasis by excessive intake of cannabis during pregnancy is associated with negative pregnancy outcomes, including preterm birth. The use of medicinal cannabis is becoming more widespread in Western countries, especially in people of reproductive age. Cannabis contains phytocannabinoids, which modulate the ECS, and emerging evidence suggests that phytocannabinoids, through their action on cannabinoid receptors, may have a negative impact on fertility, pregnancy outcome, and fetal health. In this mini-review, we highlight the recent advances in the field, which explore the role of endocannabinoids in early pregnancy and the effects of excessive intake of phytocannabinoids in pregnancy outcomes.

Download Full-text

Statins are detrimental to human placental development and function; use of statins during early pregnancy is inadvisable

Journal of Cellular and Molecular Medicine ◽

10.1111/j.1582-4934.2008.00466.x ◽

2008 ◽

Vol 12 (6a) ◽

pp. 2295-2296 ◽

Cited By ~ 17

Author(s):

Karen Forbes ◽

Lucy M. Hurst ◽

J. Martin Gibson ◽

John D. Aplin ◽

Melissa Westwood

Keyword(s):

Early Pregnancy ◽

Placental Development ◽

And Function

Download Full-text

Studies on reproduction in prolific ewes:7. Variability in the growth of individual foetuses in relation to intra-uterine factors

The Journal of Agricultural Science ◽

10.1017/s0021859600031981 ◽

1981 ◽

Vol 96 (1) ◽

pp. 187-194 ◽

Cited By ~ 9

Author(s):

I. McDonald ◽

J. J. Robinson ◽

C. Fraser

Keyword(s):

Litter Size ◽

Early Pregnancy ◽

Gestational Age ◽

Ovulation Rate ◽

Placental Development ◽

Embryo Mortality ◽

The Difference ◽

Placental Structure

SUMMARYThe weights of 44 twin foetuses, 99 triplets and 44 quadruplets, varying in gestational age from 55 to 145 days, were studied in relation to age, sex, litter size, uterine position, placental structure and weight, and ovulation rate. Triplet and quadruplet foetuses were more variable in weight, within litters, than were twins. The difference increased with foetal age and was attributed to increased competition between foetuses which were located within the same horn of the uterus. The effect was largely associated with differences in placental development, i.e. numbers of cotyledons and weight, but those differences did not entirely account for the reduction in foetal weight with increasing litter size. Differences in placental development, arising from embryo mortality, also accounted for the reduction in foetal weight when ovulation rate exceeded litter size. In contrast, differences in foetal weight associated with the sex of the foetuses were only partly mediated by differences in cotyledon weight. Foetuses in the larger litters are thus not only lighter in weight but are more variable in weight, the increased variability being controlled by events in early pregnancy.

Download Full-text

miR-146a-5p Regulated Cell Proliferation and Apoptosis by Targeting SMAD3 and SMAD4

Protein and Peptide Letters ◽

10.2174/0929866526666190911142926 ◽

2020 ◽

Vol 27 (5) ◽

pp. 411-418 ◽

Cited By ~ 1

Author(s):

Meiyu Qiu ◽

Tao Li ◽

Binhu Wang ◽

Hongbin Gong ◽

Tao Huang

Keyword(s):

Cell Proliferation ◽

Protein Expression ◽

Early Pregnancy ◽

Caspase 3 ◽

Target Genes ◽

Luciferase Reporter ◽

Bewo Cell ◽

Regulation Mechanism ◽

Placental Development ◽

Qrt Pcr

Background: microRNAs (miRNAs) are a small, endogenous non-coding RNAs that are involved in post-transcriptional gene regulation of many biological processes, including embryo implantation and placental development. In our previous study, miR-146a-5p was found expressed higher in the serum exosomes of pregnant sows than non-pregnant. The research on miR-146a-5p has been mainly related to human diseases, but there are few studies on its effects on the reproduction of sows in early pregnancy. Objective: In this article, our motivation is to study the role of miR-146a-5p in the early pregnancy of sows on the cell proliferetion and apoptosis by targeting SMAD3 and SMAD4. Methods: Bioinformatics software was used to identify the target genes of miR-146a-5p. The wildtype and mutant-type recombinant plasmids of dual-luciferase reporter with 3'-UTR of Smad3 or 3'- UTR of Smad4 were constructed, and co-transfected in porcine kidney cell (PK-15 cell) with miR- 146a-5p mimic, mimic-NC(M-NC), inhibitor and inhibitor-NC(IN-NC), then dual-luciferase activity analysis, qRT-PCR and Western blot were performed to verify the target genes. After the transfection of BeWo choriocarcinoma cell (BeWo cell) with miR-146a-5p mimic, M-NC, inhibitor and IN-NC, the mRNA expression of Caspase-3, BAX and Bcl-2 was measured using qRT-PCR, and the cell proliferation was measured using CCK-8 kit. Results: The luciferase, mRNA and protein expression of Smad3 in PK-15 cells treated by Smad3- 3'-UTR-W co-transfected with miR-146a-5p mimic were significantly lower than that with miR- 146a-5p M-NC, and the results of Smad4 were similar to Smad3, but the protein expression had a trend to lower in mimic group. The expression level of Bcl-2 in the miR-146a-5p mimic group was significantly lower than that in the miR-146a-5p M-NC group, but the expression pattern of Caspase-3 was just opposite. The mimic of miR-146a-5p reduced the proliferation of BeWo cells, however the inhibitor increased. Conclusion: Smad3 and Smad4 are the direct target genes of miR-146a-5p. The expression of Smad3 and Smad4 were affected by the mimic and inhibitor of miR-146a-5p. miR-146a-5p affects cell apoptosis and proliferation by regulating their target genes. This study provided new data to understand the regulation mechanism of early pregnancy in sows.

Download Full-text