scholarly journals Progesterone and Interferon Tau Regulate Hypoxia-Inducible Factors in the Endometrium of the Ovine Uterus

Endocrinology ◽  
2008 ◽  
Vol 149 (4) ◽  
pp. 1926-1934 ◽  
Author(s):  
Gwonhwa Song ◽  
Jinyoung Kim ◽  
Fuller W. Bazer ◽  
Thomas E. Spencer
Keyword(s):  
Estrous Cycle ◽  
Hypoxia Inducible Factor ◽  
Cell Types ◽  
Mrna Abundance ◽  
Mrna Levels ◽  
Uterine Receptivity ◽  
Blastocyst Development ◽  
Interferon Tau ◽  
Carboxy Terminal ◽  
Ovine Uterus

In ruminants, progesterone (P4) from the ovary and interferon tau (IFNT) from the elongating blastocyst regulate expression of genes in the endometrium that are hypothesized to be important for uterine receptivity and blastocyst development. These studies determined effects of the estrous cycle, pregnancy, P4, and IFNT on hypoxia-inducible factor (HIF) expression in the ovine uterus. HIF1A mRNA, HIF2A mRNA, and HIF2A protein were most abundant in the endometrial luminal and superficial glandular epithelia (LE and sGE, respectively) of the uterus and conceptus trophectoderm. During the estrous cycle, HIF1A and HIF2A mRNA levels were low to undetectable on d 10 in the endometrial LE/sGE, increased between d 10 and 14, and then declined on d 16. Both HIF1A and HIF2A mRNA were more abundant in the endometrial LE/sGE of pregnant ewes. However, HIF3A, HIF1B, HIF2B, and HIF3B mRNA abundance was low in most cell types of the endometria and conceptus. Treatment of ovariectomized ewes with P4 induced HIF1A and HIF2A in the endometrial LE/sGE, and intrauterine infusion of ovine IFNT further increased HIF2A in P4-treated ewes, but not in ewes treated with P4 and the antiprogestin ZK 136,317. HIF3A, HIF1B, HIF2B, and HIF3B mRNA abundance was not regulated by either P4 or IFNT. Two HIF-responsive genes, carboxy-terminal domain 2 and vascular endothelial growth factor A, were detected in both the endometrium and conceptus. These studies identified new P4-induced (HIF1A and HIF2A) and IFNT-stimulated (HIF2A) genes in the uterine LE/sGE, and implicate the HIF pathway in regulation of endometrial epithelial functions and angiogenesis, as well as peri-implantation blastocyst development.

Characterization and regulation of extracellular vesicles in the lumen of the ovine uterus†

2020 ◽  
Vol 102 (5) ◽  
pp. 1020-1032 ◽  
Author(s):  
Eleanore V O’Neil ◽  
Gregory W Burns ◽  
Christina R Ferreira ◽  
Thomas E Spencer
Keyword(s):  
Extracellular Vesicles ◽  
Cell Types ◽  
Size Exclusion ◽  
Rna Seq ◽  
Interferon Tau ◽  
Uterine Lumen ◽  
Pregnant Sheep ◽  
Exclusion Chromatography ◽  
Ovine Uterus

Abstract Secretions of the endometrium are vital for peri-implantation growth and development of the sheep conceptus. Extracellular vesicles (EVs) are present in the uterine lumen, emanate from both the endometrial epithelia of the uterus and trophectoderm of the conceptus, and hypothesized to mediate communication between those cell types during pregnancy establishment in sheep. Size-exclusion chromatography and nanoparticle tracking analysis determined that total EV number in the uterine lumen increased from days 10 to 14 of the cycle but was lower on days 12 and 14 of pregnancy in sheep. Intrauterine infusions of interferon tau (IFNT) did not affect total EV number in the uterine lumen. Quantitative mass spectrometric analyses defined proteins and lipids in EVs isolated from the uterine lumen of day 14 cyclic and pregnant sheep. In vitro analyses found that EVs decreased ovine trophectoderm cell proliferation and increased IFNT production without effects on gene expression as determined by RNA-seq. Collective results support the idea EVs impact conceptus growth during pregnancy establishment via effects on trophectoderm cell growth.

scholarly journals Progesterone and interferon tau regulate leukemia inhibitory factor receptor and IL6ST in the ovine uterus during early pregnancy

Reproduction ◽  
2009 ◽  
Vol 137 (3) ◽  
pp. 553-565 ◽  
Author(s):  
Gwonhwa Song ◽  
M Carey Satterfield ◽  
Jinyoung Kim ◽  
Fuller W Bazer ◽  
Thomas E Spencer
Keyword(s):  
Early Pregnancy ◽  
Leukemia Inhibitory Factor ◽  
Inhibitory Factor ◽  
Signal Transducer ◽  
Uterine Receptivity ◽  
Leukemia Inhibitory Factor Receptor ◽  
Interferon Tau ◽  
Specific Manner ◽  
Ovine Uterus ◽  
Phosphorylated Stat3

The actions of leukemia inhibitory factor (LIF) via LIF receptor (LIFR) and its co-receptor, IL6 signal transducer (IL6ST), are implicated in uterine receptivity to conceptus implantation in a number of species including sheep. The present study determined the effects of the estrous cycle, pregnancy, progesterone (P4), and interferon tau (IFNT) on the expression of LIFR and IL6ST in the ovine uterus. LIFR mRNA and protein were localized to the endometrial luminal (LE) and superficial glandular epithelia (sGE), whereas IL6ST mRNA and protein were localized primarily in the middle to deep GE. Both LIFR and IL6ST mRNAs and protein were more abundant in pregnant than cyclic ewes and increased from days 10 to 20 of pregnancy. Treatment of ovariectomized ewes with P4 and/or infusion of ovine IFNT increased LIFR and IL6ST in endometrial LE/sGE and GE respectively. Co-expression of LIFR and IL6ST as well as phosphorylated STAT3 was observed only in the upper GE of the endometrium as well as in the conceptus trophectoderm on days 18 and 20. In mononuclear trophectoderm and GE cells, LIF elicited an increase in phosphorylated STAT3 and MAPK3/1 MAPK proteins. Collectively, these results suggest that LIFR and IL6ST are both stimulated by IFNT and regulated by P4 in a complex stage- and cell-specific manner, and support the hypothesis that LIF exerts effects on the endometrial GE as well as conceptus trophectoderm during early pregnancy in sheep. Thus, LIF and STAT3 may have biological roles in endometrial function and trophectoderm growth and differentiation.

scholarly journals IOP1, a novel hydrogenase-like protein that modulates hypoxia-inducible factor-1α activity

2006 ◽  
Vol 401 (1) ◽  
pp. 341-352 ◽  
Author(s):  
Jianhe Huang ◽  
Daisheng Song ◽  
Adrian Flores ◽  
Quan Zhao ◽  
Sharon M. Mooney ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Hypoxia Inducible Factor ◽  
Cell Types ◽  
Mrna Levels ◽  
Low Oxygen ◽  
Gene Expressions ◽  
Iron Sulfur Cluster ◽  
Α Subunit ◽  
Protein Levels ◽  
Hypoxic Conditions

A central means by which mammalian cells respond to low oxygen tension is through the activation of the transcription factor HIF-1 (hypoxia-inducible factor-1). Under normoxic conditions, HIF-1α (the α subunit of HIF-1) is targeted for rapid degradation by the ubiquitin–proteasome pathway. Under hypoxic conditions, this degradation is inhibited, thereby leading to the stabilization and activation of HIF-1α. Here, we report the identification of IOP1 (iron-only hydrogenase-like protein 1), a protein homologous with enzymes present in anaerobic organisms that contain a distinctive iron–sulfur cluster. IOP1 is present in a broad range of cell types. Knockdown of IOP1 using siRNA (small interfering RNA) in mammalian cells increases protein levels of HIF-1α under both normoxic and hypoxic conditions, and augments hypoxia-induced HRE (hypoxia response element) reporter gene and endogenous HIF-1α target gene expressions. We find that IOP1 knockdown up-regulates HIF-1α mRNA levels, thereby providing a mechanism by which knockdown induces the observed effects. The results collectively provide evidence that IOP1 is a component of the protein network that regulates HIF-1α in mammalian cells.

Expression of hypoxia-inducible factor-1α in the brain of rats during chronic hypoxia

2000 ◽  
Vol 89 (5) ◽  
pp. 1937-1942 ◽  
Author(s):  
Juan C. Chávez ◽  
Faton Agani ◽  
Paola Pichiule ◽  
Joseph C. LaManna
Keyword(s):  
Mammalian Cells ◽  
Glucose Transporter ◽  
Hypoxia Inducible Factor ◽  
Arterial Oxygen Tension ◽  
Cell Types ◽  
Arterial Oxygen ◽  
Ependymal Cells ◽  
Mrna Levels ◽  
Adaptive Responses ◽  
Glucose Transporter 1

Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that regulates adaptive responses to the lack of oxygen in mammalian cells. HIF-1 consists of two proteins, HIF-1α and HIF-1β. HIF-1α accumulates under hypoxic conditions, whereas HIF-1β is constitutively expressed. HIF-1α and HIF-1β expression were measured during adaptation to hypobaric hypoxia (0.5 atm) in rat cerebral cortex. Western blot analyses indicated that HIF-1α rapidly accumulated during the onset of hypoxia and did not fall for 14 days but fell to normal by 21 days despite the continuous low arterial oxygen tension. Immunostaining showed that neurons, astrocytes, ependymal cells, and possibly endothelial cells were the cell types expressing HIF-1α. Genes with hypoxia-responsive elements were activated under these conditions, as evidenced by elevated vascular endothelial growth factor and glucose transporter-1 mRNA levels. When 21-day-adapted rats were exposed to a more severe hypoxic challenge (8% oxygen), HIF-1α accumulated again. On the basis of these results, we speculate that the vascular remodeling and metabolic changes triggered during prolonged hypoxia are capable of restoring normal tissue oxygen levels.

Temporal, spatial, and oxygen-regulated expression of hypoxia-inducible factor-1 in the lung

1998 ◽  
Vol 275 (4) ◽  
pp. L818-L826 ◽  
Author(s):  
Aimee Y. Yu ◽  
Maria G. Frid ◽  
Larissa A. Shimoda ◽  
Charles M. Wiener ◽  
Kurt Stenmark ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Hypoxia Inducible Factor ◽  
Alveolar Epithelium ◽  
Cell Types ◽  
Immunoblot Analysis ◽  
Heme Oxygenase 1 ◽  
Mrna Levels ◽  
Microvascular Endothelium ◽  
Pulmonary Arterial

Hypoxia-inducible factor (HIF)-1 is a basic helix-loop-helix transcription factor that transactivates genes encoding proteins that participate in homeostatic responses to hypoxia. Several of these downstream gene products, such as erythropoietin, vascular endothelial growth factor, heme oxygenase-1, and inducible nitric oxide synthase, may contribute to the pathogenesis of pulmonary hypertension. Previous studies demonstrated increased HIF-1 mRNA levels in rats and mice subjected to hypoxia. In this study, we have demonstrated spatial, temporal, and O2-dependent expression of HIF-1 protein. Immunoblot analysis revealed hypoxic induction of HIF-1 in all cultured pulmonary cell types assayed, including those derived from pulmonary arterial endothelium and smooth muscle, bronchial epithelium, alveolar macrophages, alveolar epithelium, and microvascular endothelium. In contrast to all other cell types, pulmonary arterial smooth muscle cells expressed HIF-1 under nonhypoxic conditions. Immunohistochemistry and immunoblot analysis of ferret lungs demonstrated pulmonary expression of HIF-1 in vivo. HIF-1 protein expression was induced maximally when lungs were ventilated with 0 or 1% O2 for 4 h. On reoxygenation, HIF-1 was rapidly degraded, with a half-life of <1 min. These findings demonstrate that HIF-1 expression is tightly coupled to O2 concentration in vivo and are consistent with the involvement of HIF-1 in the physiological and pathophysiological responses to hypoxia in the lung.

scholarly journals Several fibroblast growth factors are expressed during pre-attachment bovine conceptus development and regulate interferon-tau expression from trophectoderm

Reproduction ◽  
2009 ◽  
Vol 137 (2) ◽  
pp. 259-269 ◽  
Author(s):  
Flavia N T Cooke ◽  
Kathleen A Pennington ◽  
Qien Yang ◽  
Alan D Ealy
Keyword(s):  
Growth Factors ◽  
Fibroblast Growth Factors ◽  
Mrna Levels ◽  
Fibroblast Growth ◽  
Blastocyst Development ◽  
Interferon Tau ◽  
Trophectoderm Cells ◽  
Conceptus Development

The trophectoderm-derived factor interferon tau (IFNT) maintains the uterus in a pregnancy-receptive state in cattle and sheep. Fibroblast growth factors (FGFs) are implicated in regulatingIFNTexpression and potentially other critical events associated with early conceptus development in cattle. The overall objectives of this work were to identify the variousFGFsand FGF receptors (FGFRs) expressed in elongating pre-attachment bovine conceptuses and determine if these FGFs regulate conceptus development and/or mediate IFNT production.In vitro-derived bovine blastocysts andin vivo-derived elongated conceptuses collected at day 17 of pregnancy express at least fourFGFRsubtypes (R1c,R2b,R3c,R4). In addition, transcripts forFGF1,2, and10but notFGF7are present in elongated bovine conceptuses. The expression pattern ofFGF10most closely resembled that ofIFNT, with both transcripts remaining low in day 8 and day 11 conceptuses and increasing substantially in day 14 and day 17 conceptuses. Supplementation with recombinant FGF1, 2 or 10 increasedIFNTmRNA levels in bovine trophectoderm cells and bovine blastocysts and increased IFNT protein concentrations in trophectoderm-conditioned medium. Blastocyst development was not affected by any of the FGFs. In summary, at least four FGFRs reside in pre- and peri-attachment bovine conceptuses. Moreover, conceptuses express at least three candidate FGFs during elongation, the time of peakIFNTexpression. These findings provide new insight for how conceptus-derived factors such as FGF1, 2, and 10 may controlIFNTexpression during early pregnancy in cattle.

scholarly journals Effects of differentn-6:n-3 fatty acid ratios and of enterolactone on gene expression and PG secretion in bovine endometrial cells

2014 ◽  
Vol 113 (1) ◽  
pp. 56-71 ◽  
Author(s):  
Catherine Hallé ◽  
Alan K. Goff ◽  
Hélène V. Petit ◽  
Richard Blouin ◽  
Marie-France Palin
Keyword(s):  
Gene Expression ◽  
Fatty Acid ◽  
Culture Media ◽  
Cell Types ◽  
Mrna Abundance ◽  
Uterine Receptivity ◽  
Embryo Survival ◽  
Endometrial Stromal Cells ◽  
Endometrial Cells ◽  
Positive Effects

Feeding flaxseed to dairy cows can modulate gene expression and PG synthesis in the uterus at the time of peri-implantation. The objectives of the present study were to determine which flaxseed components are responsible for these effects and how different endometrial cell types are affected. We evaluated the effects of six different linoleic acid (n-6):α-linolenic acid (n-3) ratios and three concentrations of the lignan enterolactone (ENL) on endometrial stromal cells (SC) and epithelial cells (EC). The mRNA abundance of genes with known or suspected roles in embryo survival or PG synthesis was evaluated, along with PGE2and PGF2αconcentrations in culture media. The mRNA abundance of several genes was modulated by different fatty acid (FA) ratios and/or ENL, and this modulation differed between cell types. The FA4 (FA at ann-6:n-3 ratio of 4) treatment (rich inn-3 FA) increased the mRNA abundance of genes that have positive effects on uterine receptivity and implantation when compared with the FA25 (FA at ann-6:n-3 ratio of 25) treatment (rich inn-6 FA). ENL decreased PGE2and PGF2αconcentrations in both cell types, and this reduction was associated with lower mRNA abundance of the PG synthase genesAKR1B1andPTGESin SC. The combination of ENL with FA (FA4 treatment) resulted in the greatest reduction in PGF2αconcentrations when compared with the addition of FA (FA4) or ENL alone. Because of the known luteolytic properties of PGF2α, a reduction in endometrial PGF2αsecretion would favour the establishment and maintenance of pregnancy.

Novel aspects of endometrial function: a biological sensor of embryo quality and driver of pregnancy success

2012 ◽  
Vol 24 (1) ◽  
pp. 68 ◽  
Author(s):  
Olivier Sandra ◽  
Nadéra Mansouri-Attia ◽  
Richard G. Lea
Keyword(s):  
Developmental Stages ◽  
Assisted Reproductive Technologies ◽  
Uterine Cavity ◽  
Reproductive Technologies ◽  
Biological Properties ◽  
Reproductive Capacity ◽  
Epigenetic Alterations ◽  
Uterine Receptivity ◽  
Blastocyst Development ◽  
Developmental Potential

Successful pregnancy depends on complex biological processes that are regulated temporally and spatially throughout gestation. The molecular basis of these processes have been examined in relation to gamete quality, early blastocyst development and placental function, and data have been generated showing perturbations of these developmental stages by environmental insults or embryo biotechnologies. The developmental period falling between the entry of the blastocyst into the uterine cavity to implantation has also been examined in terms of the biological function of the endometrium. Indeed several mechanisms underlying uterine receptivity, controlled by maternal factors, and the maternal recognition of pregnancy, requiring conceptus-produced signals, have been clarified. Nevertheless, recent data based on experimental perturbations have unveiled unexpected biological properties of the endometrium (sensor/driver) that make this tissue a dynamic and reactive entity. Persistent or transient modifications in organisation and functionality of the endometrium can dramatically affect pre-implantation embryo trajectory through epigenetic alterations with lasting consequences on later stages of pregnancy, including placentation, fetal development, pregnancy outcome and post-natal health. Developing diagnostic and prognostic tools based on endometrial factors may enable the assessment of maternal reproductive capacity and/or the developmental potential of the embryo, particularly when assisted reproductive technologies are applied.

Transmembrane prolyl 4-hydroxylase is a fourth prolyl 4-hydroxylase regulating EPO production and erythropoiesis

Blood ◽  
2012 ◽  
Vol 120 (16) ◽  
pp. 3336-3344 ◽  
Author(s):  
Anu Laitala ◽  
Ellinoora Aro ◽  
Gail Walkinshaw ◽  
Joni M. Mäki ◽  
Maarit Rossi ◽  
...  
Keyword(s):  
Cultured Cells ◽  
Mrna Level ◽  
Hypoxia Inducible Factor ◽  
Mrna Levels ◽  
Wild Type ◽  
Α Subunit ◽  
Hepcidin Expression ◽  
In The Wild ◽  
Hepcidin Mrna

AbstractAn endoplasmic reticulum transmembrane prolyl 4-hydroxylase (P4H-TM) is able to hydroxylate the α subunit of the hypoxia-inducible factor (HIF) in vitro and in cultured cells, but nothing is known about its roles in mammalian erythropoiesis. We studied such roles here by administering a HIF-P4H inhibitor, FG-4497, to P4h-tm−/− mice. This caused larger increases in serum Epo concentration and kidney but not liver Hif-1α and Hif-2α protein and Epo mRNA levels than in wild-type mice, while the liver Hepcidin mRNA level was lower in the P4h-tm−/− mice than in the wild-type. Similar, but not identical, differences were also seen between FG-4497–treated Hif-p4h-2 hypomorphic (Hif-p4h-2gt/gt) and Hif-p4h-3−/− mice versus wild-type mice. FG-4497 administration increased hemoglobin and hematocrit values similarly in the P4h-tm−/− and wild-type mice, but caused higher increases in both values in the Hif-p4h-2gt/gt mice and in hematocrit value in the Hif-p4h-3−/− mice than in the wild-type. Hif-p4h-2gt/gt/P4h-tm−/− double gene-modified mice nevertheless had increased hemoglobin and hematocrit values without any FG-4497 administration, although no such abnormalities were seen in the Hif-p4h-2gt/gt or P4h-tm−/− mice. Our data thus indicate that P4H-TM plays a role in the regulation of EPO production, hepcidin expression, and erythropoiesis.

scholarly journals A possible role for hypoxia-induced apelin expression in enteric cell proliferation

2008 ◽  
Vol 294 (6) ◽  
pp. R1832-R1839 ◽  
Author(s):  
Song Han ◽  
Guiyun Wang ◽  
Xiang Qi ◽  
Heung M. Lee ◽  
Ella W. Englander ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Epithelial Cell ◽  
Intestinal Inflammation ◽  
Acute Hypoxia ◽  
Hypoxia Inducible Factor ◽  
Mrna Levels ◽  
Epithelial Cell Proliferation ◽  
Gi Tract ◽  
Rat Pups

Apelin is the endogenous ligand for the APJ receptor, and apelin and APJ are expressed in the gastrointestinal (GI) tract. Intestinal inflammation increases intestinal hypoxia-inducible factor (HIF) and apelin expression. Hypoxia and inflammation are closely linked cellular insults. The purpose of these studies was to investigate the influence of hypoxia on enteric apelin expression. Exposure of rat pups to acute hypoxia increased hepatic, stomach-duodenal, and colonic apelin mRNA levels 10-, 2-, and 2-fold, respectively ( P < 0.05 vs. controls). Hypoxia also increased colonic APJ mRNA levels, and apelin treatment during hypoxia exposure enhanced colonic APJ mRNA levels further. In vitro hypoxia also increased apelin and APJ mRNA levels. The hypoxia-induced elevation in apelin expression is most likely mediated by HIF, since HIF-activated apelin transcriptional activity is dependent on an intact, putative HIF binding site in the rat apelin promoter. Acute exposure of rat pups to hypoxia lowered gastric and colonic epithelial cell proliferation; hypoxia in combination with apelin treatment increased epithelial proliferation by 50%. In vitro apelin treatment of enteric cells exposed to hypoxia increased cell proliferation. Apelin treatment during normoxia was ineffective. Our studies imply that the elevation in apelin expression during hypoxia and inflammation in the GI tract functions in part to stimulate epithelial cell proliferation.

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