scholarly journals SMAD Signaling Is Required for Structural Integrity of the Female Reproductive Tract and Uterine Function During Early Pregnancy in Mice

2016 ◽  
Vol 95 (2) ◽  
pp. 44-44 ◽  
Author(s):  
A. Rodriguez ◽  
S. K. Tripurani ◽  
J. C. Burton ◽  
C. Clementi ◽  
I. Larina ◽  
...  
2010 ◽  
Vol 22 (9) ◽  
pp. 108
Author(s):  
R. G. Craythorn ◽  
W. R. Winnall ◽  
M. P. Hedger ◽  
P. A. W. Rogers ◽  
D. M. De Kretser ◽  
...  

Follistatin acts by binding and neutralising the activity of activin-A, which has important regulatory roles in development, reproduction and inflammation. There are two isoforms of follistatin comprising 288 and 315 amino acids (FST288 and FST315), resulting from alternative gene splicing. FST288 binds spontaneously to heparan sulphate and is largely bound to cell surface proteoglycans. FST315 is the predominant circulating form and can only bind to heparan sulphate after binding activin-A. The regulation of these splice variants in the female reproductive tract have not been investigated in detail. In this study, our aim was to quantify the expression of FST288 and FST315 mRNA in the mouse uterus during early pregnancy (days 1–4, pre-implantation), and in response to exogenous oestradiol-17b (100 ng × single s.c. injection, dissection after 24 h) and progesterone (1 mg × three daily s.c. injections, dissection 24 h after last injection) in ovariectomised mice. Gene expression was analysed using quantitative RT-PCR. Primers amplifying a product from exon 5 to 6a (unique to FST288) or from exon 5 to 6b (unique to FST315) were used to discriminate the isoforms. In early pregnancy, expression of both FST288 and FST315 increased significantly (approximately 35-fold and 100-fold, respectively) on days 3–5, relative to days 1–2, corresponding with the increase in circulating progesterone levels that occurs at day 3. A significant increase in FST288 and FST315 mRNA expression (both approximately 35-fold) was also observed in ovariectomised mice in response to exogenous progesterone, but there was no increase in response to oestradiol-17β. In contrast to the similar rate of increase in response to exogenous progesterone, FST315 mRNA expression increased more rapidly than FS288 in early pregnancy, indicating that differential regulation of the two isoforms also occurs. We conclude that progesterone regulates both FST288 and FST315 mRNA expression during early pregnancy in the mouse uterus.


2005 ◽  
Vol 230 (3) ◽  
pp. 189-199 ◽  
Author(s):  
Izabela Wolawek-Potocka ◽  
Mamadou M. Bah ◽  
Anna Korzekwa ◽  
Mariusz K. Piskula ◽  
Wieslaw Wiczkowski ◽  
...  

Phytoestrogens acting as endocrine disruptors may induce various pathologies in the female reproductive tract. The purpose of this study was to determine whether phytoestrogens present in the soybean and/or their metabolites are detectable in the plasma of cows fed a diet rich in soy and whether these phytoestrogens influence reproductive efficiency and prostaglandin (PG) synthesis during the estrous cycle and early pregnancy in the bovine endometrium. In in vivo Experiment 1, we found significant levels of daidzein and genistein in the fodder and their metabolites (equol and p-ethyl-phenol) in bovine serum and urine. The mean number of artificial inseminations (Als) and pregnancy rates in two kinds of herds, control and experimental (cows fed with soybean 2.5 kg/day), were almost double in the soy-diet herd in comparison with the control animals. In in vivo Experiment 2, three out of five heifers fed soybean (2.5 kg/day) became pregnant whereas four out of five heifers in the control group became pregnant. The concentrations of a metabolite of PGF2α (PGFM) were significantly higher in the blood plasma of heifers fed a diet rich in soybean than those in the control heifers throughout the first 21 days after ovulation and AI. The higher levels of PGFM were positively correlated with equol and p-ethyl phenol concentrations in the blood. In in vitro experiments, the influence of isoflavones on PG secretion in different stages of the estrous cycle was studied. Although all phytoestrogens augmented the output of both PGs throughout the estrous cycle, equol and p-ethyl-phenol preferentially stimulated PGF2α output. The results obtained lead to the conclusion that soy-derived phytoestrogens and their metabolites disrupt reproductive efficiency and uterus function by modulating the ratio of PGF2α to PGE2, which leads to high, nonphysiological production of luteolytic PGF2α in cattle during the estrous cycle and early pregnancy.


2021 ◽  
Author(s):  
Karen V. Lithgow ◽  
Vienna C.H. Buchholz ◽  
Emily Ku ◽  
Shaelen Konschuh ◽  
Ana D'Aubeterre ◽  
...  

Porphyromonas asaccahrolytica and Porphyromonas uenonis are frequently isolated from the human vagina and are linked to bacterial vaginosis and preterm labour. However, little is known about the pathogenesis mechanisms of these bacteria. The related oral opportunistic pathogen, Porphyromonas gingivalis, is comparatively well-studied and known to secrete numerous extracellular matrix-targeting proteases. Among these are the gingipain family of cysteine proteases that drive periodontal disease progression and hematogenic transmission to the placenta. Given their phylogenetic relatedness, we hypothesized that vaginal Porphyromonas species possess gingipain-like protease activity targeting host extracellular matrix in the female reproductive tract. In this study, we demonstrate that vaginal Porphyromonas species degrade type I collagen (cervix), type IV collagen (chorioamnion/placenta), and fibrinogen, but not through the activity of gingipain orthologs. Bioinformatic queries identified five candidate collagenases in each species, including serine, cysteine and metalloproteases, with signal peptides directing them to the extracellular environment. Inhibition assays revealed both species secrete metalloproteases that degrade collagen and casein, while P. asaccharolytica also secretes a metalloprotease that degrades fibrinogen. Phylogenetic analysis of the predicted collagen-degrading metalloprotease revealed an orthologous relationship with the P. gingivalis endopeptidase PepO. Cloning and expression of P. asaccharolytica PepO confirmed this protein's collagenase and caseinase activities, which have not previously been attributed to PepO homologs in other bacteria. Altogether, this description of the first known virulence factor in Porphyromonas species colonizing the human vagina sheds light on their potential to alter the structural integrity and homeostasis of reproductive tissues.


2019 ◽  
Vol 1 (2) ◽  
pp. 49-60
Author(s):  
Sophonie Jean ◽  
Bernice Huang ◽  
Hardik I. Parikh ◽  
David J. Edwards ◽  
J. Paul Brooks ◽  
...  

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nan Ni ◽  
Xin Fang ◽  
Qinglei Li

AbstractTransforming growth factor β (TGFβ) signaling plays critical roles in reproductive development and function. TGFβ ligands signal through the TGFβ receptor type 2 (TGFBR2)/TGFBR1 complex. As TGFBR2 and TGFBR1 form a signaling complex upon ligand stimulation, they are expected to be equally important for propagating TGFβ signaling that elicits cellular responses. However, several genetic studies challenge this concept and indicate that disruption of TGFBR2 or TGFBR1 may lead to contrasting phenotypic outcomes. We have shown that conditional deletion of Tgfbr1 using anti-Mullerian hormone receptor type 2 (Amhr2)-Cre causes oviductal and myometrial defects. To determine the functional requirement of TGFBR2 in the female reproductive tract and the potential phenotypic divergence/similarity resulting from conditional ablation of either receptor, we generated mice harboring Tgfbr2 deletion using the same Cre driver that was previously employed to target Tgfbr1. Herein, we found that conditional deletion of Tgfbr2 led to a similar phenotype to that of Tgfbr1 deletion in the female reproductive tract. Furthermore, genetic removal of Tgfbr1 in the Tgfbr2-deleted uterus had minimal impact on the phenotype of Tgfbr2 conditional knockout mice. In summary, our results reveal the functional similarity between TGFBR2 and TGFBR1 in maintaining the structural integrity of the female reproductive tract.


Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3776-3776
Author(s):  
Mario von Depka ◽  
Mahnaz Ekhlasi-Hundrieser ◽  
Carsten Detering ◽  
Stefanie Lehner ◽  
Christiane Pfarrer ◽  
...  

Abstract Objectives: Clinical studies showed that women affected by von Willebrand disease (VWD) trend towards higher rates of miscarriages, but the underlying pathomechanisms remain unclear. Several in vitro studies demonstrated an influence of von Willebrand factor (VWF) on angiogenesis, which seems to be partly mediated via VEGF. Since angiogenesis in the reproductive organs is essential to establish and maintain pregnancy, we aimed to investigate gene expression of VWF, VEGF, and its receptor VEGFR2 in non-pregnant and pregnant individuals, using a porcine model of VWD type 1. Methods: Tissue samples of uterus, oviduct and ovary were harvested from eight female pigs of which four were pregnant on day 30 (time of placentation) and four were non-pregnant and in estrus. Of each group, two were affected by VWD type 1 and two were wildtype (WT) individuals. The gene expression of VWF, VEGF, and VEGFR2 was measured by qRT-PCR and relatively quantified against the endothelial specific housekeeping genes PROCR and CD31 using the ΔΔCT method and calculating the respective x-fold changes. The gene expression differences were compared between both genotypes as well as between both reproductive states Mean differences were taken into account, if the divergences were consistent in both individuals of each group and not within the range of the group they were compared to. Results: Regarding the non-pregnant sows, VWF expression was lower in uterus and ovary of the VWD type 1 animals. This difference was not seen comparing the pregnant animals of each genotype, but the VWD type 1 animals showed higher VEGF expression in oviduct and higher VEGF and VEGFR2 expression in the ovary. The expression of VEGFR2 was reduced in the uterus. Comparing the non-pregnant with the pregnant animals within each genotype, the following results were found: the pregnant WT pigs showed increased expression of VEGFR2 in uterus and ovary, but decreased expression of VEGF in the uterus. For the pregnant VWD type 1 animals increased expression was found for VWF and VEGFR2 in the ovary, and decreased expression for VEGF in uterus and oviduct and VEGFR2 in the uterus. Discussion and Conclusion: Comparison of the different groups revealed differences of gene expression in the female reproductive tract during early pregnancy. The expectedly lower expression of VWF in the VWD type 1 animals was not found for the pregnant animals. Apparently, there is an increase of VWF levels during pregnancy as seen in women. While VEGFR2 expression in the uterus increases during placentation in the WT animals, it decreases in the VWD type 1 animals. This suggests altered regulation of early angiogenesis, which is essential during placentation. Expression of VEGF and VEGFR2 was increased in the ovaries of the VWD type 1 animals. This points to an enhanced involvement of this pathway during conversion of the ruptured follicles to sufficient corpora lutea graviditates, which may affect this process. Enhanced angiogenesis via the VEGF/VEGFR2-pathway due to lack of VWF was already shown in vitro. Our study shows that the expression of VEGF and VEGFR2 differs during early pregnancy in VWD type 1 compared to wildtype sows. Therefore, this pathway may influence angiogenesis in the reproductive tract. Disclosures No relevant conflicts of interest to declare.


2013 ◽  
Vol 25 (1) ◽  
pp. 207
Author(s):  
H. L. Sánchez-Rodríguez ◽  
J. M. Feugang ◽  
R. C. Youngblood ◽  
R. C. Vann ◽  
S. T. Willard ◽  
...  

Vasodilation of the female reproductive vasculature is essential to supply the increasing demands associated with reproductive processes; including maintenance of a healthy functional luteal structure, and the establishment and continuance of pregnancy. Due to its vasodilatory effects, prostaglandin E2 has been identified as a potential candidate sustaining such vascular effects. Here, the relationship between systemic concentrations of prostaglandin E2 metabolite (PGEM) and progesterone (P4), and uterine arterial vasodilatory changes were evaluated during the oestrous cycle and early pregnancy. Synchronised Angus cows (n = 19) were artificially inseminated (AI) and examined for pregnancy 45 d post-AI. Jugular blood samples were collected on Days 0, 3, 6, 10, 16, 20, 25, and 32 (Day 0 = AI) for serum PGEM and P4 evaluation. Vasodilatory changes of the uterine arteries were also characterised using the B-mode ultrasound luminal circumference (UAC). Retrospective comparisons were carried out between pregnant (n = 10) and nonpregnant (n = 9) animals. The GLM Procedure of SAS (SAS Institute Inc., Cary, NC, USA) was used to evaluate the effects of pregnancy status and sampling day over PGEM, UAC, and P4. Pearson correlations between PGEM, UAC, and P4 were obtained by the CORR Procedure of SAS. All variables were measured in triplicate and thresholds for significance and tendency were fixed at P ≤ 0.05 and 0.06 to 0.10, respectively. From Day 0 to Day 20, the overall PGEM concentration tended to be higher in nonpregnant cows compared to pregnant ones (P = 0.08; 90.97 ± 4.38 v. 78.28 ± 3.01 pg mL–1, respectively), while a shift in favor of pregnant cows was observed at Day 32 (P = 0.29; 89.88 ± 14.23 v. 106.3 ± 7.17 pg mL–1, respectively). Both uterine arteries showed similar UAC (P ≥ 0.05); therefore, they were combined in one average value per animal each sampling day. There was an overall increase of the UAC over time, from 10.49 ± 0.01 mm at Day 0 to 12.17 ± 0.02 mm at Day 20 (P ≤ 0.0001), but no significant differences were found between pregnant and nonpregnant cows during this period (P ≥ 0.05). An overall sharp increase in P4 concentrations was observed from Day 3 to Day 16 (0.60 ± 0.12 to 9.66 ± 0.45 ng mL–1, P ≤ 0.0001); while from Day 16 to Day 32, pregnant cows maintained steady and higher P4 concentrations than nonpregnant ones (9.87 ± 0.31 v. 4.40 ± 1.09 ng mL–1, respectively; P = 0.002). As expected, nonpregnant cows showed a sharp decrease in P4 concentrations from Day 16 to Day 25, followed by a second increase at Day 32 (9.27 ± 0.20, 0.85 ± 0.33, and 6.04 ± 1.67 ng mL–1, respectively; P = 0.0007). The UAC and PGEM concentrations were positively correlated in pregnant (r = 0.48; P = 0.002), but not in nonpregnant animals (r = 0.29; P = 0.21). Similarly, UAC and P4 concentrations were also positively associated in pregnant (r = 0.47; P = 0.002), but not in nonpregnant cows (r = 0.01; P = 0.96). Our findings support the role of PGE2 as a potential mediator of the vascular function in the female reproductive tract and, subsequently, as an essential factor to ensure adequate P4 production able to sustain early pregnancy in the bovine. USDA-ARS Grant#58-6402-3-0120.


2005 ◽  
Vol 17 (9) ◽  
pp. 121
Author(s):  
D. J. Glynn ◽  
S. A. Robertson

An inflammatory cascade is elicited in the female reproductive tract following mating in mice. The recruited leukocytes and cytokines have roles in facilitating implantation through activating immunological tolerance and endometrial tissue remodelling. We have previously shown that seminal plasma acts to induce synthesis of GM-CSF and IL-6 in the female reproductive tract in response to TGFβ1 present in seminal fluid. Recently we have shown that chemokines, specifically the neutrophil chemoattractant KC, is dramatically upregulated after mating. The purpose of this study was to identify the active constituent of semen responsible for KC induction. Female mice were mated with either intact, seminal vesicle deficient or vasectomized males and uterine flushings were collected approximately 8 h later, when KC content was measured by specific ELISA. KC production was increased 13-fold, 6-fold and 10-fold respectively, indicating that neither the seminal plasma nor the sperm fraction of semen was necessary for induction. To investigate more precisely the identity of the KC inducing factor, an in vitro primary uterine epithelial cell culture system was employed. Uterine epithelial cells were harvested from estrous female mice and exposed to a range of doses of seminal vesicle fluid, TGFβ1or lipopolysaccharide (LPS). Following addition of seminal vesicle fluid or TGFβ1 KC production was decreased by 100% and 58% respectively whereas it was increased ~2-fold in response to LPS. Together these data indicate that LPS derived from the male or lower female reproductive tract accessing the uterus after insemination is required for KC induction, and implicate commensal bacteria as having a key regulatory role in the cellular and molecular quality of the uterine immune environment during early pregnancy.


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