scholarly journals Inhibition of the C-X-C Motif Chemokine 12 (CXCL12) and Its Receptor CXCR4 Reduces Utero-Placental Expression of the VEGF System and Increases Utero-Placental Autophagy

2021 ◽  
Vol 8 ◽  
Author(s):  
Ryan L. Ashley ◽  
Cheyenne L. Runyan ◽  
Marlie M. Maestas ◽  
Elisa Trigo ◽  
Gail Silver
Keyword(s):  
Cross Sections ◽  
Vascular Endothelial ◽  
Placental Development ◽  
Cxcr4 Antagonist ◽  
Cxcr4 Signaling ◽  
Placental Dysfunction ◽  
Autophagy Induction ◽  
Underlying Causes ◽  
Endothelial Growth Factor ◽  
Development Result

The placenta, a unique organ that only develops during pregnancy, is essential for nutrient, oxygen, and waste exchange between offspring and mother. Yet, despite its importance, the placenta remains one of the least understood organs and knowledge of early placental formation is particularly limited. Abnormalities in placental development result in placental dysfunction or insufficiency whereby normal placental physiology is impaired. Placental dysfunction is a frequent source of pregnancy loss in livestock, inflicting serious economic impact to producers. Though the underlying causes of placental dysfunction are not well-characterized, initiation of disease is thought to occur during establishment of functional fetal and placental circulation. A comprehensive understanding of the mechanisms controlling placental growth and vascularization is necessary to improve reproductive success in livestock. We propose chemokine C-X-C motif ligand 12 (CXCL12) signaling through its receptor CXCR4 functions as a chief coordinator of vascularization through direct actions on fetal trophoblast and maternal endometrial and immune cells. To investigate CXCL12–CXCR4 signaling on uteroplacental vascular remodeling at the fetal–maternal interface, we utilized a CXCR4 antagonist (AMD3100). On day 12 post-breeding in sheep, osmotic pumps were surgically installed and delivered either AMD3100 or saline into the uterine lumen ipsilateral to the corpus luteum for 14 days. On day 35 of ovine pregnancy, fetal/placental and endometrial tissues were collected, snap-frozen in liquid nitrogen, and uterine horn cross sections were preserved for immunofluorescent analysis. Suppressing CXCL12–CXCR4 at the fetal–maternal interface during initial placental vascularization resulted in diminished abundance of select angiogenic factors in fetal and maternal placenta on day 35. Compared to control, less vascular endothelial growth factor (VEGF) and VEFG receptor 2 (KDR) were observed in endometrium when CXCL12–CXCR4 was diminished. Less VEGF was also evident in fetal placenta (cotyledons) in ewes receiving AMD3100 infusion compared to control. Suppressing CXCL12–CXCR4 at the fetal–maternal interface also resulted in greater autophagy induction in fetal and maternal placenta compared to control, suggestive of CXCL12–CXCR4 impacting cell survival. CXCL12–CXCR4 signaling may govern placental homeostasis by serving as a critical upstream mediator of vascularization and cell viability, thereby ensuring appropriate placental development.

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.

Early predictors of placental dysfunction

2016 ◽  
pp. 25-28
Author(s):  
J.M. Melnik ◽  
◽  
A.A. Shlyahtina ◽  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Pregnant Women ◽  
Umbilical Artery ◽  
Placental Growth Factor ◽  
Vascular Endothelial ◽  
Endothelin 1 ◽  
Placental Dysfunction ◽  
Early Predictors ◽  
Endothelial Growth Factor

The article presents the predictors of placental dysfunction on the early stage of pregnancy. The objective: the search for prognostic markers and criteria for the occurrence of placental insufficiency in the early stages of the gestational process to optimize the pregnancy and labor with improved perinatal outcomes. Patients and methods. To solve this goal in the period from 2013 to 2015 were conducted a comprehensive survey of 334 pregnant women, which depending on the peculiarities of pregnancy and childbirth were divided into groups. The control group consisted of 236 pregnant women with uncomplicated gestational period, no morphological signs of placental dysfunction. The study group included 98 patients with a complicated pregnancy who had revealed violations of the fetal-placental relations, which was confirmed by morphological examination of the placenta in the postpartum period. Results. It was found that pregnant women with placental insufficiency in the first trimester of pregnancy have higher levels of interleukin-1B (IL-1v) and interleukin-3 (IL-3) in comparison with physiological pregnancy, as well as there is a direct significant correlation between IL-1v and pulsative index (PI) in the spiral (r=0.84) and uterine artery (r=0.77), and the inverse correlation between the level of IL-3 and PI in the terminal branches of the umbilical artery (r=-0.69). Verified an inverse relationship between the concentration of endothelin-1, the level of vascular endothelial growth factor (r=-0.87) and placental growth factor (r=-0.73), and also a direct link between the content of endothelin-1 and PI in spiral arteries (r=0.89), uterine artery (r=0.83) and the terminal branches of the umbilical artery (r=0.79). Conclusion. Thus, it is proven that early predictors of placental dysfunction can be considered the concentration of endothelin-1, vascular endothelial growth factor, placental growth factor, interleukin-1, interleukin-3, and the indices of pulsative index. Key words: placental dysfunction, predictors, endothelin-1, vascular endothelial growth factor, placental growth factor, interleukin, pulsative index.

scholarly journals Comparison of expression patterns for placenta growth factor, vascular endothelial growth factor (VEGF), VEGF-B and VEGF-C in the human placenta throughout gestation

1998 ◽  
Vol 159 (3) ◽  
pp. 459-467 ◽  
Author(s):  
DE Clark ◽  
SK Smith ◽  
D Licence ◽  
AL Evans ◽  
DS Charnock-Jones
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Expression Patterns ◽  
In Situ Hybridisation ◽  
Extravillous Trophoblast ◽  
Vascular Endothelial ◽  
Placenta Growth Factor ◽  
Placental Development ◽  
New Members ◽  
Endothelial Growth Factor

Angiogenesis and vascular transformation are important processes in the normal development of the placenta. Vascular endothelial growth factor (VEGF) is a potent angiogenic growth factor and is thought to be important for placental development. Recently several new members of this family have been described. In this study we used in situ hybridisation to localise which cells in the placenta expressed mRNA for VEGF, placenta growth factor (PlGF), VEGF-B and VEGF-C. We were unable to find any message for either VEGF-B or VEGF-C in the placenta, suggesting that only low levels are produced which this method was unable to detect. The mRNA encoding VEGF was found to be produced by cells within the villous mesenchyme, decidual macrophages and decidual glands but, in contrast to our previous findings, not by trophoblast. The mRNA encoding PlGF was produced in large amounts by villous cytotrophoblast, syncytiotrophoblast and extravillous trophoblast. The mRNAs encoding VEGF and PlGF were thus not co-localised and it appears that there is unlikely to be any significant production of VEGF/PlGF heterodimer in the placenta.

scholarly journals N-carbamylglutamate and L-arginine improved maternal and placental development in underfed ewes

Reproduction ◽  
2016 ◽  
Vol 151 (6) ◽  
pp. 623-635 ◽  
Author(s):  
Hao Zhang ◽  
Lingwei Sun ◽  
Ziyu Wang ◽  
Mingtian Deng ◽  
Haitao Nie ◽  
...  
Keyword(s):  
Growth Factor ◽  
Dietary Supplementation ◽  
Late Gestation ◽  
Vascular Endothelial ◽  
Placental Development ◽  
Fetal Plasma ◽  
Total Antioxidant ◽  
Endocrine Status ◽  
Endothelial Growth Factor ◽  
Hu Sheep

AbstractThe objectives of this study were to determine how dietary supplementation ofN-carbamylglutamate (NCG) and rumen-protected L-arginine (RP-Arg) in nutrient-restricted pregnant Hu sheep would affect (1) maternal endocrine status; (2) maternal, fetal, and placental antioxidation capability; and (3) placental development. From day 35 to day 110 of gestation, 32 Hu ewes carrying twin fetuses were allocated randomly into four groups: 100% of NRC-recommended nutrient requirements, 50% of NRC recommendations, 50% of NRC recommendations supplemented with 20g/day RP-Arg, and 50% of NRC recommendations supplemented with 5g/day NCG product. The results showed that in maternal and fetal plasma and placentomes, the activities of total antioxidant capacity and superoxide dismutase were increased (P<0.05); however, the activity of glutathione peroxidase and the concentration of maleic dialdehyde were decreased (P<0.05) in both NCG- and RP-Arg-treated underfed ewes. The mRNA expression of vascular endothelial growth factor and Fms-like tyrosine kinase 1 was increased (P<0.05) in 50% NRC ewes than in 100% NRC ewes, and had no effect (P>0.05) in both NCG- and RP-Arg-treated underfed ewes. A supplement of RP-Arg and NCG reduced (P<0.05) the concentrations of progesterone, cortisol, and estradiol-17β; had no effect on T4/T3; and improved (P<0.05) the concentrations of leptin, insulin-like growth factor 1, tri-iodothyronine (T3), and thyroxine (T4) in serum from underfed ewes. These results indicate that dietary supplementation of NCG and RP-Arg in underfed ewes could influence maternal endocrine status, improve the maternal–fetal–placental antioxidation capability, and promote fetal and placental development during early-to-late gestation.

Temporal candidate gene expression in the sow placenta and embryo during early gestation and effect of maternal Progenos supplementation on embryonic and placental development

2012 ◽  
Vol 24 (4) ◽  
pp. 550 ◽  
Author(s):  
S. Novak ◽  
F. Paradis ◽  
J. L. Patterson ◽  
J. A. Pasternak ◽  
K. Oxtoby ◽  
...  
Keyword(s):  
Gene Expression ◽  
Muscle Development ◽  
Nutritional Supplement ◽  
Vascular Endothelial ◽  
Placental Development ◽  
Early Gestation ◽  
Beneficial Effects ◽  
Critical Phases ◽  
Embryonic Muscle Development ◽  
Endothelial Growth Factor

The present study characterised gene expression associated with embryonic muscle development and placental vascularisation during early gestation in the pig and examined effects of Progenos supplementation in early pregnancy. Tissues were collected from commercial multiparous sows (n = 48) from Days 16 to 49 of gestation. In the placenta, qPCR revealed that vascular endothelial growth factor (VEGFA) expression did not change from Day 17 to 49 of gestation; however, KDR receptor and angiopoietin-1 and -2 expression were differentially regulated, with periods of high expression corresponding to two critical phases of angiogenesis in the pig. In the embryo, the pattern of myogenesis-related gene expression was consistent with available literature. A commercially available nutritional supplement Progenos (20 g day–1 l-arginine) added to the diet of sows from either Day 15 to 29 (P15–29; n = 33), Day 30 to 44 (n = 29) or from Day 15 to 44 (n = 76) of gestation tended to increase (P = 0.058) embryonic growth rate compared with non-supplemented controls (n = 79) and angiogenin expression was higher (P = 0.028) at Day 30 of gestation in placentae from sows on the P15–29 Progenos treatment. These results are consistent with proposed beneficial effects of l-arginine on early embryonic development and placental vascularisation.

63 Inhibition of CXCR4 at the fetal-maternal interface during placentation results in altered production of vascular endothelial growth factor receptors in the placenta on Day 90 of pregnancy

2020 ◽  
Vol 32 (2) ◽  
pp. 157
Author(s):  
J. M. Ervin ◽  
S. Z. McIntosh ◽  
C. L. Runyan ◽  
R. L. Ashley
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Animal Model ◽  
Growth Factor ◽  
Day Treatment ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Placental Development ◽  
Fetal Survival ◽  
Pregnant Sheep ◽  
Endothelial Growth Factor

Placental development is characterised by extensive angiogenesis and vascularization; if these processes are compromised, placental dysfunction occurs, which is the underlying cause of complications such as preeclampsia and intrauterine growth restriction. The signalling axis initiated by chemokine ligand 12 (CXCL12) and its receptor CXCR4 stimulate angiogenesis critical to placental vascularization. Our laboratory and others demonstrated stimulation of vascular endothelial growth factor (VEGF) synthesis by CXCL12/CXCR4 signalling, and recently, we reported less production of the VEGF receptor, FLT-1, on Day 20 in pregnant sheep following interference of intrauterine CXCL12-dependent signalling. While no animal model fully recapitulates human placentation, the sheep is arguably the most applicable animal model to study fetal-maternal interactions and placentation. Based on our studies, we hypothesised that inhibiting CXCR4 at the fetal-maternal interface during initial placentation alters placental production of VEGF receptors, FLT-1 and KDR, at mid-gestation. To test this hypothesis, AMD3100, a CXCR4 antagonist, was used to elucidate the role of CXCL12/CXCR4 signalling at the ovine fetal-maternal interface. On Day 12 post-breeding, osmotic pumps were surgically installed and delivered either AMD3100 or phosphate-buffered saline (PBS) into the uterine lumen ipsilateral to the corpus luteum for either 7 days (n=7 PBS and n=8 AMD3100) or 14 days (n=7 PBS and n=8 AMD3100). The objectives were to determine whether disruption of the CXCL12/CXCR4 axis during placentation affects fetal survival and alters VEGF receptor synthesis and whether duration of CXCR4 inhibition affects placental vascular remodelling. On Day 90 of pregnancy, ewes were anaesthetised; reproductive tracts were removed; and maternal caruncle (CAR) and fetal cotyledon (COT) components were separated, snap frozen in liquid nitrogen, and stored at −80°C until protein isolation. Pregnancy success was not affected by treatment or duration of treatment (71% PBS vs. 62% AMD3100 for 7 days; 85% PBS vs. 62% AMD3100 for 14 days). In addition, fetal weight on Day 90 (530.8±28.2 g PBS vs. 540.5±20.3g AMD3100 for 7 days; 494.3±23.9g PBS vs. 532.7±11.8g AMD3100 for 14 days) was not affected by treatment. Immunoblotting was used to detect protein abundance, and an unpaired two-tailed Student's t-test was used to determine significant changes. Greater FLT-1 (P&lt;0.05) was evident in CAR and COT tissue on Day 90 for both the 7-day treatment (0.92±0.16 CAR PBS vs. 1.48±0.18 CAR AMD3100; 0.12±0.16 COT PBS vs. 0.62±0.16 COT AMD3100) and the 14-day treatment (0.18±0.05 CAR PBS vs. 0.43±0.001 CAR AMD3100; 0.04±0.005 COT PBS vs. 0.11±0.02 COT AMD3100) of CXCR4 inhibition compared with controls, whereas KDR levels did not change (P&gt;0.05). Interestingly, elevated FLT-1, but not KDR, is a marker of preeclampsia in women, and because of its role as a VEGF scavenger, overexpression of FLT-1 often leads to an anti-angiogenic state. We suggest that CXCL12/CXCR4 signalling during initial placental development serves as an upstream regulator of placental vascularization, thereby ensuring appropriate placental development.

scholarly journals VEGF Triggers Transient Induction of Autophagy in Endothelial Cells via AMPKα1

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 687 ◽  
Author(s):  
Katrin Spengler ◽  
Nderim Kryeziu ◽  
Silke Große ◽  
Alexander S. Mosig ◽  
Regine Heller
Keyword(s):  
Endothelial Cells ◽  
Autophagic Flux ◽  
Vascular Endothelial ◽  
Bafilomycin A1 ◽  
Autophagosome Formation ◽  
Ampk Pathway ◽  
Notch Intracellular Domain ◽  
Autophagy Induction ◽  
Amp Activated Protein Kinase ◽  
Endothelial Growth Factor

AMP-activated protein kinase (AMPK) is activated by vascular endothelial growth factor (VEGF) in endothelial cells and it is significantly involved in VEGF-induced angiogenesis. This study investigates whether the VEGF/AMPK pathway regulates autophagy in endothelial cells and whether this is linked to its pro-angiogenic role. We show that VEGF leads to AMPKα1-dependent phosphorylation of Unc-51-like kinase 1 (ULK1) at its serine residue 556 and to the subsequent phosphorylation of the ULK1 substrate ATG14. This triggers initiation of autophagy as shown by phosphorylation of ATG16L1 and conjugation of the microtubule-associated protein light chain 3B, which indicates autophagosome formation; this is followed by increased autophagic flux measured in the presence of bafilomycin A1 and by reduced expression of the autophagy substrate p62. VEGF-induced autophagy is transient and probably terminated by mechanistic target of rapamycin (mTOR), which is activated by VEGF in a delayed manner. We show that functional autophagy is required for VEGF-induced angiogenesis and may have specific functions in addition to maintaining homeostasis. In line with this, inhibition of autophagy impaired VEGF-mediated formation of the Notch intracellular domain, a critical regulator of angiogenesis. Our study characterizes autophagy induction as a pro-angiogenic function of the VEGF/AMPK pathway and suggests that timely activation of autophagy-initiating pathways may help to initiate angiogenesis.

scholarly journals Deletion of Vascular Endothelial Growth Factor C (VEGF-C) and VEGF-D Is Not Equivalent to VEGF Receptor 3 Deletion in Mouse Embryos

2008 ◽  
Vol 28 (15) ◽  
pp. 4843-4850 ◽  
Author(s):  
Paula Haiko ◽  
Taija Makinen ◽  
Salla Keskitalo ◽  
Jussi Taipale ◽  
Marika J. Karkkainen ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Early Embryo ◽  
Vegf Receptor ◽  
Tissue Fluid ◽  
Vascular Endothelial ◽  
Placental Development ◽  
Independent Functions ◽  
Factor C ◽  
Endothelial Growth Factor

ABSTRACT Lymphatic vessels play an important role in the regulation of tissue fluid balance, immune responses, and fat adsorption and are involved in diseases including lymphedema and tumor metastasis. Vascular endothelial growth factor (VEGF) receptor 3 (VEGFR-3) is necessary for development of the blood vasculature during early embryogenesis, but later, VEGFR-3 expression becomes restricted to the lymphatic vasculature. We analyzed mice deficient in both of the known VEGFR-3 ligands, VEGF-C and VEGF-D. Unlike the Vegfr3 −/− embryos, the Vegfc −/−; Vegfd −/− embryos displayed normal blood vasculature after embryonic day 9.5. Deletion of Vegfr3 in the epiblast, using keratin 19 (K19) Cre, resulted in a phenotype identical to that of the Vegfr3 −/− embryos, suggesting that this phenotype is due to defects in the embryo proper and not in placental development. Interestingly, the Vegfr3 neo hypomorphic mutant mice carrying the neomycin cassette between exons 1 and 2 showed defective lymphatic development. Overexpression of human or mouse VEGF-D in the skin, under the K14 promoter, rescued the lymphatic hypoplasia of the Vegfc +/− mice in the K14-VEGF-D; Vegfc +/− compound mice, suggesting that VEGF-D is functionally redundant with VEGF-C in the stimulation of developmental lymphangiogenesis. Our results suggest VEGF-C- and VEGF-D-independent functions for VEGFR-3 in the early embryo.

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