CXCR4 signaling at the fetal–maternal interface may drive inflammation and syncytia formation during ovine pregnancy†

2020 ◽  
Author(s):  
Stacia Z McIntosh ◽  
Marlie M Maestas ◽  
Jordyn R Dobson ◽  
Kelsey E Quinn ◽  
Cheyenne L Runyan ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Placental Development ◽  
Cxcr4 Signaling ◽  
Proinflammatory Mediators ◽  
Placental Angiogenesis ◽  
Precise Understanding ◽  
Chemokine Ligand ◽  
Syncytia Formation ◽  
Complex Signaling ◽  
Surface Remodeling

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.

scholarly journals CXCR4 signaling at the ovine fetal–maternal interface regulates vascularization, CD34+ cell presence, and autophagy in the endometrium†

2019 ◽  
Vol 101 (1) ◽  
pp. 102-111 ◽  
Author(s):  
Cheyenne L Runyan ◽  
Stacia Z McIntosh ◽  
Marlie M Maestas ◽  
Kelsey E Quinn ◽  
Ben P Boren ◽  
...  
Keyword(s):  
Cross Sections ◽  
Angiogenic Factors ◽  
Placental Development ◽  
Cxcr4 Antagonist ◽  
Cxcr4 Signaling ◽  
Cellular Autophagy ◽  
Signaling Axis ◽  
Chemokine Ligand ◽  
Clinical Consequences ◽  
Ovine Fetal

Abstract Placenta development is characterized by extensive angiogenesis and vascularization but if these processes are compromised placental dysfunction occurs, which is the underlying cause of pregnancy complications such as preeclampsia and intrauterine growth restriction. Dysregulation of placental angiogenesis has emerged as one of the main pathophysiological features in the development of placental insufficiency and its clinical consequences. The signaling axis initiated by chemokine ligand 12 (CXCL12) and its receptor CXCR4 stimulates angiogenesis in other tissues, and may be central to placental vascularization. We hypothesized that CXCL12-CXCR4 signaling governs the pro-angiogenic placental microenvironment by coordinating production of central angiogenic factors and receptors and regulates endometrial cell survival essential for placental function and subsequent fetal longevity. The CXCR4 antagonist, AMD3100, was used to elucidate the role of CXCL12-CXCR4 signaling regarding uteroplacental vascular remodeling at the fetal–maternal interface. On day 12 postbreeding, osmotic pumps were surgically installed and delivered either AMD3100 or PBS into the uterine lumen ipsilateral to the corpus luteum. On day 20, endometrial tissues were collected, snap-frozen in liquid nitrogen, and uterine horn cross sections preserved for immunofluorescent analysis. In endometrium from ewes receiving AMD3100 infusion, the abundance of select angiogenic factors was diminished, while presence of CD34+ cells increased compared to control ewes. Ewes receiving AMD3100 infusion also exhibited less activation of Akt/mTOR signaling, and elevated LC3B-II, a marker of cellular autophagy in endometrium. This study suggests that CXCL12-CXCR4 signaling governs placental homeostasis by serving as a critical upstream mediator of vascularization and cell viability, thereby ensuring appropriate placental development.

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

Reproduction ◽  
2010 ◽  
Vol 140 (1) ◽  
pp. 165-174 ◽  
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.

106 ANGIOGENIC FACTOR mRNA EXPRESSION IN FETAL MEMBRANES IN EARLY PREGNANT SHEEP

2009 ◽  
Vol 21 (1) ◽  
pp. 153
Author(s):  
M. L. Johnson ◽  
L. P. Reynolds ◽  
M. A. Minten ◽  
P. P. Borowicz ◽  
D. A. Redmer ◽  
...  
Keyword(s):  
Growth Factor ◽  
Vascular Development ◽  
Fetal Loss ◽  
Angiogenic Factor ◽  
Fetal Membranes ◽  
Detailed Knowledge ◽  
Placental Development ◽  
Vegf Mrna ◽  
Placental Angiogenesis ◽  
Pregnant Sheep

Maternal and fetal placental development may be compromised by use of assisted reproductive techniques, including cloning, resulting in poor placental angiogenesis and subsequent high embryonic/fetal loss (Palmieri et al. 2007 Placenta 28, 577–584). Before changes in vascular development in placenta from compromised pregnancies can be understood, a detailed knowledge of regulation of angiogenesis in placental tissues from normal pregnancies is necessary. Therefore, this study determined the expression pattern of mRNA for several angiogenic factors and their receptors: vascular endothelial growth factor (VEGF) and receptor (R) 1 and 2; basic fibroblast growth factor (FGF2) and FGFRIIIc; angiopoietin (ANGPT) 1 and 2 and ANGPTR (Tie2); endothelial nitric oxide synthase (eNOS) and NO receptor GUCY1B3 in fetal membranes (FM; fetal placenta) collected on Days 16, 18, 20, 22, 24, 26, 28, and 30 after mating (n = 5 to 8/day). Fetal membranes were snap frozen for evaluation of gene expression using quantitative, real-time RT-PCR. VEGF mRNA was increased (P < 0.05) 2-fold on Days 28 and 30 compared with Days 16, 18, and 20, whereas VEGFR1 mRNA increased (P < 0.05) 25- to 50-fold on Days 28 and 30 compared with Day 16, and VEGFR2 mRNA was greatest (P < 0.05) on Day 22 compared with Days 16, 18, 28, and 30. FGF2 mRNA was 4-fold greater (P < 0.05) on Day 22 compared with Day 16; however, FGF2RIIIc was unchanged from Day 16 through 30. eNOS mRNA was greatest (P < 0.05) on Days 22 and 24 compared with Days 16 and 18, but GUCY1B3 mRNA was greatest (P < 0.05) on Day 18 compared with Days 20, 24, and 28. ANGPT1 mRNA increased (P < 0.05) 40-fold by Days 28 and 30 compared with Days 16 and 18. ANGPT2 mRNA was undetectable on Day 16, and increased (P < 0.05) 5-fold from Days 18 through 30. ANGPTR mRNA was greatest (P < 0.05) on Days 22 and 24 compared with Days 16 and 18. This description of expression of factors potentially regulating early placental angiogenesis during normal pregnancy in sheep will provide the foundation for understanding the dramatic increases in capillary cell proliferation and capillary size we have previously observed (unpublished) and for determining whether placental vascular development is altered in compromised pregnancies. USDA-NRI grant 2007-01215 to LPR and ATGB; NIH grant HL64141 to LPR and DAR; ND EPSCoR AURA grant to ATGB and MAM; ND Space Grant Fellowship Program award to MAM; and NIH grant P20 RR016741 (INBRE program of the NCRR, NIH).

scholarly journals Involvement of the Intrarenal Renin-Angiotensin System in Experimental Models of Glomerulonephritis

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Maki Urushihara ◽  
Yukiko Kinoshita ◽  
Shuji Kondo ◽  
Shoji Kagami
Keyword(s):  
Blood Pressure ◽  
Intracellular Signaling ◽  
Renin Angiotensin System ◽  
Experimental Models ◽  
At1 Receptor ◽  
Biologically Active ◽  
Ang Ii ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Proinflammatory Mediators

The intrarenal renin-angiotensin system (RAS) has several pathophysiologic functions not only in blood pressure regulation but also in the development of glomerulonephritis (GN). Angiotensin II (Ang II) is the biologically active product of the RAS. Locally produced Ang II induces inflammation, renal cell growth, mitogenesis, apoptosis, migration, and differentiation, regulates the gene expression of bioactive substances, and activates multiple intracellular signaling pathways, leading to tissue damage. Activation of the Ang II type 1 (AT1) receptor pathway results in the production of proinflammatory mediators, cell proliferation, and extracellular matrix synthesis, which facilitates glomerular injury. Previous studies have shown that angiotensin-converting enzyme inhibitors and/or AT1 receptor blockers have beneficial effects in experimental GN models and humans with various types of GN, and that these effects are more significant than their suppressive effects on blood pressure. In this paper, we focus on intrarenal RAS activation in the pathophysiology of experimental models of GN.

scholarly journals PPARγ in Placental Angiogenesis

Endocrinology ◽  
2010 ◽  
Vol 151 (10) ◽  
pp. 4969-4981 ◽  
Author(s):  
Karim Nadra ◽  
Laure Quignodon ◽  
Chiara Sardella ◽  
Elisabeth Joye ◽  
Antonio Mucciolo ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Late Pregnancy ◽  
Peroxisome Proliferator ◽  
Placental Development ◽  
Peroxisome Proliferator Activated Receptor ◽  
Placental Angiogenesis ◽  
Pparγ Agonist ◽  
Vascular Proliferation ◽  
Knockout Animals ◽  
Endothelial Growth Factor

Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor involved in diverse biological processes including adipocyte differentiation, glucose homeostasis, and inflammatory responses. Analyses of PPARγ knockout animals have been so far preempted by the early embryonic death of PPARγ−/− embryos as a consequence of the severe alteration of their placental vasculature. Using Sox2Cre/PPARγL2/L2 mice, we obtained fully viable PPARγ-null mice through specific and total epiblastic gene deletion, thereby demonstrating that the placental defect is the unique cause of PPARγ−/− embryonic lethality. The vasculature defects observed in PPARγ−/− placentas at embryonic d 9.5 correlated with an unsettled balance of pro- and antiangiogenic factors as demonstrated by increased levels of proliferin (Prl2c2, PLF) and decreased levels of proliferin-related protein (Prl7d1, PRP), respectively. To analyze the role of PPARγ in the later stage of placental development, when its expression peaks, we treated pregnant wild-type mice with the PPARγ agonist rosiglitazone. This treatment resulted in a disorganization of the placental layers and an altered placental microvasculature, accompanied by the decreased expression of proangiogenic genes such as Prl2c2, vascular endothelial growth factor, and Pecam1. Together our data demonstrate that PPARγ plays a pivotal role in controlling placental vascular proliferation and contributes to its termination in late pregnancy.

CXCL14 antagonizes the CXCL12-CXCR4 signaling axis

2014 ◽  
Vol 5 (2) ◽  
pp. 167-173 ◽  
Author(s):  
Takahiko Hara ◽  
Kosuke Tanegashima
Keyword(s):  
Primordial Germ Cells ◽  
Antagonistic Activity ◽  
Receptor Internalization ◽  
Fine Tuning ◽  
Amino Acid Residues ◽  
Hematopoietic Stem ◽  
Cxcr4 Signaling ◽  
Anti Cancer ◽  
Signaling Axis ◽  
Chemokine Ligand

AbstractCXCL12 and CXCL14 are evolutionarily conserved members of the CXC-type chemokine family. CXCL12 binds specifically to the G-protein-coupled receptor CXCR4 to induce the migration of primordial germ cells, hematopoietic stem cells, and inflammation-associated immune cells. In addition, CXCL12-CXCR4 signaling is often enhanced in malignant tumor cells and facilitates increased proliferation as well as metastasis. Although macrophage migration inhibitory factor and extracellular ubiquitin interact with CXCR4 as agonistic factors, CXCL12 was believed to be the sole chemokine ligand for CXCR4. However, a very recent report revealed that CXCL14 binds to CXCR4 with high affinity and efficiently inhibits CXCL12-mediated chemotaxis of hematopoietic progenitor and leukemia-derived cells. CXCL14 does not directly cross-compete with CXCL12 for the CXCR4 binding but instead inactivates CXCR4 via receptor internalization. Because both CXCL12 and CXCL14 are expressed during embryogenesis and brain development in mice, these two chemokines could function in an interactive fashion. We propose that the CXCL14 gene has been conserved from fish to man due to its role in fine-tuning the strength of CXCL12-mediated signal transduction. In addition to its biological implications, the above finding will be important for designing anti-cancer compounds targeting the CXCL12-CXCR4 signaling axis. In fact, a stabilized dimeric peptide containing the C-terminal 51–77 amino acid residues of CXCL14 has been shown to have stronger CXCL12 antagonistic activity than full-length CXCL14.

scholarly journals Angiogenesis in the Placenta: The Role of Reactive Oxygen Species Signaling

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Robyn D. Pereira ◽  
Nicole E. De Long ◽  
Ruijun C. Wang ◽  
Fereshteh T. Yazdi ◽  
Alison C. Holloway ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Transcription Factors ◽  
Maternal Obesity ◽  
Placental Development ◽  
Placental Dysfunction ◽  
Placental Angiogenesis ◽  
Healthy Pregnancy ◽  
Adverse Pregnancy ◽  
And Function ◽  
Reactive Oxygen Species Signaling

Proper placental development and function are central to the health of both the mother and the fetus during pregnancy. A critical component of healthy placental function is the proper development of its vascular network. Poor vascularization of the placenta can lead to fetal growth restriction, preeclampsia, and in some cases fetal death. Therefore, understanding the mechanisms by which uterine stressors influence the development of the placental vasculature and contribute to placental dysfunction is of central importance to ensuring a healthy pregnancy. In this review we discuss how oxidative stress observed in maternal smoking, maternal obesity, and preeclampsia has been associated with aberrant angiogenesis and placental dysfunction resulting in adverse pregnancy outcomes. We also highlight that oxidative stress can influence the expression of a number of transcription factors important in mediating angiogenesis. Therefore, understanding how oxidative stress affects redox-sensitive transcription factors within the placenta may elucidate potential therapeutic targets for correcting abnormal placental angiogenesis and function.

scholarly journals Expression and function of CXCL12/CXCR4 in rat urinary bladder with cyclophosphamide-induced cystitis

2010 ◽  
Vol 298 (3) ◽  
pp. F589-F600 ◽  
Author(s):  
Lauren Arms ◽  
Beatrice M. Girard ◽  
Margaret A. Vizzard
Keyword(s):  
Urinary Bladder ◽  
Tissue Injury ◽  
Bladder Capacity ◽  
Rat Urinary Bladder ◽  
Cxcr4 Signaling ◽  
Qrt Pcr ◽  
Proinflammatory Mediators ◽  
Bladder Inflammation ◽  
And Function

Chemokines, otherwise known as chemotactic cytokines, are proinflammatory mediators of the immune response and have been implicated in altered sensory processing, hyperalgesia, and central sensitization following tissue injury or inflammation. To address the role of CXCL12/CXCR4 signaling in normal micturition and inflammation-induced bladder hyperreflexia, bladder inflammation in adult female Wistar rats (175–250 g) was induced by injecting cyclophosphamide (CYP) intraperitoneally at acute (150 mg/kg; 4 h), intermediate (150 mg/kg; 48 h), and chronic (75 mg/kg; every 3rd day for 10 days) time points. CXCL12, and its receptor, CXCR4, were examined in the whole urinary bladder of control and CYP-treated rats using enzyme-linked immunosorbent assays (ELISAs), quantitative PCR (qRT-PCR), and immunostaining techniques. ELISAs, qRT-PCR, and immunostaining experiments revealed a significant ( P ≤ 0.01) increase in CXCL12 and CXCR4 expression in the whole urinary bladder, and particularly in the urothelium, with CYP treatment. The functional role of CXCL12/CXCR4 signaling in micturition was evaluated using conscious cystometry with continuous instillation of saline and CXCR4 receptor antagonist (AMD-3100; 5 μM) administration in control and CYP (48 h)-treated rats. Receptor blockade of CXCR4 using AMD-3100 increased bladder capacity in control (no CYP) rats and reduced CYP-induced bladder hyperexcitability as demonstrated by significant ( P ≤ 0.01) increases in intercontraction interval, bladder capacity, and void volume. These results suggest a role for CXCL12/CXCR4 signaling in both normal micturition and with bladder hyperreflexia following bladder inflammation.

The Potential Role of Pro-Inflammatory and Anti-Inflammatory Cytokines in Epilepsy Pathogenesis

2020 ◽  
Vol 20 ◽  
Author(s):  
Ali N. Kamali ◽  
Zeineb Zian ◽  
José M. Bautista ◽  
Haleh Hamedifar ◽  
Nikoo Hossein-Khannazer ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Intracellular Signaling ◽  
Transforming Growth Factor ◽  
Brain Disorder ◽  
Necrosis Factor Alpha ◽  
Proinflammatory Mediators ◽  
Inflammatory Protein ◽  
Cytokine Levels ◽  
Inflammatory Processes ◽  
Factor Alpha

Abstract:: Within the pathophysiology of epilepsy, as a chronic brain disorder, neuroinflammation has been extensively implied. Recurrent seizures of epilepsy have been associated with elevated levels of immune mediators that seem to play a pivotal role in triggering them. Neurons, glia, and endothelial cells of the blood-brain barrier (BBB) take part in such inflammatory processes by expressing receptors of associated mediators through autocrine and paracrine stimulation of intracellular signaling pathways. In this milieu, elevated cytokine levels in serum and brain tissue have been reported in patients with an epileptic profile. Noteworthy, interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α) are the proinflammatory cytokines mostly associated, in literature, with the pathogenesis of epilepsies. In this review, we examine the function of these cytokines in connection with transforming growth factor-beta (TGF-β), IL-8, IL-12, IL-18, and macrophage inflammatory protein (MIP) as potential proinflammatory mediators in the neuropathology of epilepsy.

scholarly journals Rabies Virus Stimulates Nitric Oxide Production and CXC Chemokine Ligand 10 Expression in Macrophages through Activation of Extracellular Signal-Regulated Kinases 1 and 2

2004 ◽  
Vol 78 (17) ◽  
pp. 9376-9388 ◽  
Author(s):  
Kazuo Nakamichi ◽  
Satoshi Inoue ◽  
Tomohiko Takasaki ◽  
Kinjiro Morimoto ◽  
Ichiro Kurane
Keyword(s):  
Nitric Oxide ◽  
Rabies Virus ◽  
Expression Profiles ◽  
Mitogen Activated Protein Kinase ◽  
Proinflammatory Mediators ◽  
Cytokines And Chemokines ◽  
Extracellular Signal ◽  
Cxc Chemokine ◽  
Mitogen Activated Protein ◽  
Chemokine Ligand

ABSTRACT Macrophages represent an essential part of innate immunity, and the viral infection of macrophages results in the release of multiple proinflammatory mediators, such as nitric oxide (NO), cytokines, and chemokines. This study was undertaken to define the molecular mechanism of macrophage activation in response to rabies virus (RV) infection. In RAW264 murine macrophage cells, a well-characterized macrophage model, RV replication was strictly restricted, whereas cell proliferation was significantly enhanced upon RV inoculation. Transcriptional analyses for the expression of inducible forms of NO synthase (iNOS), cytokines, and chemokines revealed that RV virions potentiate the gene expression of iNOS and CXC chemokine ligand 10 (CXCL10), a major chemoattractant of T helper cell type 1. However, RV stimulation had little or no effect on the expression profiles of proinflammatory cytokines and other types of chemokines. In macrophages stimulated with UV-inactivated RV virions, as well as infectious viruses, the phosphorylation of extracellular signal-regulated kinase (ERK) 1 and 2, members of the mitogen-activated protein kinase family, was significantly induced. Specific inhibitors of MAPK/ERK kinase reduced the RV-induced production of NO and CXCL10. Furthermore, the RV-induced activation of the ERK1/2 pathway was severely impaired by the neutralization of the endosomal and lysosomal pH environment with lysosomotropic agents, indicating that endocytosis is a key step leading to the activation of ERK1/2 signaling. Taken together, these results suggest that the ERK1/2-mediated signaling pathway plays a cardinal role in the selective activation of macrophages in response to RV virions, thereby regulating cellular functions during virus infection.

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