UMLS:C0242706 - FACTA Search

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Query: UMLS:C0242706 (hyperoxia)
5,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Retinopathy of prematurity (ROP) is initiated by hyperoxia-induced obliteration of newly formed blood vessels in the retina of the premature newborn. We propose that vessel regression is a consequence of hyperoxia-induced withdrawal of a critical vascular survival factor. We show that regression of retinal capillaries in neonatal rats exposed to high oxygen, is preceded by a shut-off of vascular endothelial growth factor (VEGF) production by nearby neuroglial cells. Vessel regression occurs via selective apoptosis of endothelial cells. Intraocular injection of VEGF at the onset of experimental hyperoxia prevents apoptotic death of endothelial cells and rescues the retinal vasculature. These findings provide evidence for a specific angiogenic factor acting as a vascular survival factor in vivo. The system also provides a paradigm for vascular remodelling as an adaptive response to an increase in oxygen tension and suggests a novel approach to prevention of ROP.
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PMID:Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity. 748 57

Early placental development occurs in an environment of relative hypoxia. Hypoxia promotes angiogenesis and up-regulates vascular endothelial growth factor (VEGF) expression while it down-regulates placenta growth factor (PIGF) that possess 53% homology with VEGF. Morphological studies show poor placental vascular development and an increase in the mitotic index of cytotrophoblasts in intrauterine growth restriction (IUGR). We hypothesized that the reported relatively high oxygen level in the intervillous space in contact with IUGR placental villi will limit angiogenesis by changes in VEGF and PIGF expression and function. Western immunoblot analysis demonstrates a diametric expression of PIGF and VEGF proteins throughout pregnancy with PIGF levels increasing and VEGF levels decreasing, consistent with placental oxygenation. In IUGR placentae, the ratio of PIGF/GAPDH mRNA was increased by 2.3-fold (p < 0.03) and PIGF protein levels were also increased, (p < 0.05) as compared with gestationally-matched normal placentae. PIGF mRNA and protein were localized to the trophoblast bilayer and villous mesenchyme of the human placenta throughout gestation. In vitro studies demonstrated that increasing oxygen tension (hyperoxia) up-regulated PIGF protein in term placental villous explants, whereas hypoxic culture of a term trophoblast choriocarcinoma cell line (BeWo) down-regulated PIGF mRNA and protein and VEGFR-1 (Flt-1) autophosphorylation. The addition of PIGF-1 to a spontaneously transformed first trimester cytotrophoblast cell line stimulated DNA synthesis while PIGF-2 had little effect. VEGF and PIGF exert their biological actions by means of a common receptor VEGFR-1. In the first trimester trophoblast cells, PIGF-1 increased the association of phosphorylated extracellular signal-related kinase (ERK) with VEGFR-1 immunoprecipitates while both PIGF-1 and PIGF-2 also potentiated endogenous VEGF mediated association of phosphorylated extracellular related kinase (ERK) with VEGFR-2 (KDR). More importantly, the addition of PIGF-1 had little effect while PIGF-2 inhibited cell growth in cultured endothelial cells derived from human umbilical vein. Nitric oxide (NO) is reported to promote angiogenesis and PIGF-2 inhibited the basal release of NO from the first trimester trophoblast. The tissue expression and functional studies support the hypothesis of "placental hyperoxia" in early-onset IUGR because hypoxia down-regulates trophoblast PIGF levels, PIGF expression is increased in IUGR, and PIGF-2 inhibits endothelial cell growth. Taken together, these changes provide a cellular explanation for the observed poor angiogenesis in the pathogenesis of IUGR and show that the two PIGF isoforms may modulate trophoblast and endothelial cell function differently, possibly through potentiation of VEGF mediated activation of VEGF-2.
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PMID:Hypoxia down-regulates placenta growth factor, whereas fetal growth restriction up-regulates placenta growth factor expression: molecular evidence for "placental hyperoxia" in intrauterine growth restriction. 1006 4

Hypoxia is known to stimulate vascular growth by up-regulating vascular endothelial growth factor (VEGF), but little is known about the function of hypoxia in the development of the coronary vasculature, and the relationship between hypoxia and VEGF in this event. To test the effects of hypoxia and VEGF on coronary vasculogenesis/angiogenesis in the developing heart, ventricles from 6-day-old quail embryos were cultured on three-dimensional collagen gels. After 2 days of growth in normal medium and 1 day of starvation in low serum medium (0.5% fetal bovine serum), the heart explants were further cultured under various oxygen levels for another 24, 48, and 72 hr. Angioblasts and endothelial cells, which migrated out from the heart explants, were identified by QH1 antibody using immunofluorescence and confocal microscopy. In the normoxic culture environment, the endothelial cells began to proliferate and migrate out from the heart explants after 3 days of growth; they formed tubes mainly after another 72 hr. In contrast, this vascular growth was accelerated under hypoxic conditions, as evidenced by increased tube formation with significant differences observed at 48 hr. On the other hand, hyperoxia delayed this process. Reverse transcription-polymerase chain reaction results indicated that VEGF (including VEGF(122), VEGF(166), and VEGF(190)) was up-regulated in the heart explants under hypoxia and down-regulated under hyperoxia. VEGF neutralizing antibody added to the culture medium partially blocked this vascular growth. We conclude from this study that hypoxia can stimulate or up-regulate coronary vasculogenesis/angiogenesis and that VEGF signaling plays a major role in this event. Dev Dyn 1999;216:28-36.
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PMID:Stimulation of coronary vasculogenesis/angiogenesis by hypoxia in cultured embryonic hearts. 1047 63

Morphological studies show poor placental vascular development and an increase in the mitotic index of cytotrophoblast cells in intrauterine growth restriction (IUGR). We hypothesized that the reported relatively high oxygen level in the intervillous space in contact with IUGR placental villi will limit angiogenesis by changes in vascular endothelial growth factor (VEGF) and placenta growth factor (PIGF) expression and function. Western immunoblot analysis demonstrates a diametric expression of PIGF and VEGF proteins throughout pregnancy, with P1GF levels increasing and VEGF levels decreasing, consistent with placental oxygenation. PIGF mRNA and protein is increased in IUGR as compared to gestationally matched normal placentae. Increasing oxygen tension upregulates P1GF protein in term placental villous explants, whereas hypoxia downregulates P1GF and VEGFR-1 (Flt-1) autophosphorylation in term trophoblast choriocarcinoma cell line (BeWo). Levels of soluble Flt-1 (sFlt-1) protein in supernatant of term villous explants were upregulated by 1 per cent hypoxia, whereas hyperoxia (40 per cent) decreased sFlt-1 levels, indicating that under conditions of increasing oxygen tension, PlGF function may remain unopposed. The addition of PlGF-1 to a spontaneously transformed first trimester cytotrophoblast cell line (ED27) stimulated cell proliferation while PlGF-2 had little effect. In contrast, the addition of PlGF-1 had little effect on endothelial cell proliferation while this was inhibited by PIGF-2. Taken together these changes provide a molecular explanation for the observed poor angiogenesis in the pathogenesis of IUGR.
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PMID:Regulation of placental vascular endothelial growth factor (VEGF) and placenta growth factor (PIGF) and soluble Flt-1 by oxygen--a review. 1083 Nov 17

The goal of this study was to monitor the vascular bed during the lag phase in growth of implanted spheroids as a model of tumor dormancy. Vascular development and tumor growth were followed up by magnetic resonance imaging in a model system of MLS ovarian carcinoma spheroids implanted subcutaneously in female nude mice. Apparent vessel density in a 1-mm rim surrounding the spheroid was evaluated by gradient echo imaging as a measure of the angiogenic potential of the tumor. Vascular functionality and maturation were assessed by signal intensity changes in response to hyperoxia (elevated oxygen) and hypercapnia (elevated carbon dioxide), respectively. Tumor growth was delayed by 12 to 57 days after implantation. During this long period in which tumor volume did not change, up to 6 cycles of vascular development and regression were observed. We propose here that dynamic remodeling of the vascular bed may precede exit of tumors from dormancy. The sustained oscillations in the angiogenic response to the implanted spheroid are consistent with hypoxic regulation of vascular endothelial growth factor (VEGF), combined with the role of VEGF as an essential survival factor for newly formed blood vessels. Vascular maturation, manifested by physiological vasodilatory response to carbon dioxide, may be important for conferring vascular stability and exit from dormancy.
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PMID:Dynamic remodeling of the vascular bed precedes tumor growth: MLS ovarian carcinoma spheroids implanted in nude mice. 1093 77

Co-ordinated development of the fetal villous tree of the placenta is necessary for continued fetal growth and well-being. Before fetal viability, blood vessel development within the developing immature intermediate villi (IIV) is characterized by branching angiogenesis, such that the placenta expands to produce 10-16 generations of stem villi. Once fetal viability is attained, a developmental switch occurs to form large numbers of gas-exchanging terminal villi (TV) by non-branching angiogenesis in mature intermediate villi (MIV). Several growth factors, including vascular endothelial growth factor (VEGF), placenta growth factor (PlGF), angiopoietins, and angiostatins are produced within the villi and act locally, via their receptors, to control angiogenesis. Their relative contributions to placental vascular development are not fully understood at the present time. Severe early-onset intrauterine growth restriction (IUGR) is characterized by absent/reversed end-diastolic flow velocity (ARED) in the umbilical arteries, leading to fetal hypoxia, acidosis and a substantial rise in perinatal mortality and morbidity. The placentas from such cases show a deficit in peripheral villous development, which may be perpetuated by the effects of oxygen (delivered by maternal blood into the intervillous space) upon VEGF-directed angiogenesis, the so-called 'placental hyperoxia' theory of villous maldevelopment. Trophoblast apoptosis is a significant feature of early-onset IUGR and may explain poor flow-independent transfer of nutrients to the fetus. Finally, since transgenic mouse studies highlight the importance of trophoblast-derived transcription factors for placental villous (labyrinth) development, it is possible that the villous trophoblast controls the orderly development of the underlying mesoderm and blood vessels into the fetal villi.
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PMID:Development of the placental villous tree and its consequences for fetal growth. 1098 32

Oxygen is crucial to aerobic metabolism, but excesses of oxygen or reactive oxygen species (ROS) can injure cells. This minireview addresses two transcription factors that regulate several cellular responses to oxygen tension. Hypoxia inducible factor-1 (HIF-1) is a heterodimeric protein activated by hypoxia. Levels of HIF-1 are regulated by removal of the HIF-1alpha subunit through ubiquination and proteasomal destruction under normoxic conditions. Hypoxia inhibits the ubiquination of HIF-1alpha, preventing its destruction and allowing it to bind to hypoxia-responsive elements in gene promoter, enhancer, and intronic sequences. HIF-1 induces the expression of the hypoxia responsive genes vascular endothelial growth factor and erythropoietin. Its dysregulation has been implicated in von Hippel-Lindau disease. Nuclear factor kappaB (NFkappaB) is a family of pleotropic, dimeric transcription factors, and has a complex pattern of regulation. Under normoxic conditions, NFkappaB is bound to one of several inhibitory proteins (e.g., IkappaB) that prevent its nuclear translocation. Hyperoxia or elevations of ROS cause the ubiquination and destruction of the inhibitory proteins, freeing NFkappaB and allowing it to bind to target gene promoters. Hyperoxia in cell and animal models and acute lung injury in humans induce the expression of multiple proinflammatory cytokines through NFkappaB-dependent mechanisms. Although HIF-1 and NFkappaB respond to changes in pO(2), the precise nature of the oxygen sensing and transduction pathways is unclear in both cases. Both heme-protein and redox-sensitive mechanisms have been proposed. Improved understanding of oxygen-sensitive gene regulation may suggest targeted therapies for human disease.
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PMID:Oxygen regulation of gene expression: a study in opposites. 1100 29

Development of microvascular networks is set to meet the metabolic requirements of the tissue they perfuse. Accordingly, impairment of oxygen homeostasis, either due to increased oxygen consumption or as a result of blood vessel occlusion, triggers compensatory neovascularization. This feedback reaction is mediated by a hypoxia- and hypoglycemia-induced vascular endothelial growth factor (VEGF). VEGF accumulates under stress as a result of increased hypoxia-inducible factor-1alpha-mediated transcription, stabilization of the mRNA, and the function of a hypoxia-refractory internal ribosome entry site within its 5'-untranslated region. Matching of vascular density to the metabolic needs of the tissue may include a process of hyperoxia-induced vessel regression. Thus newly formed vascular networks may undergo a natural process of vascular pruning that takes place whenever VEGF, acting as a vascular survival factor, is downregulated below the level required to sustain immature vessels. Immature vessels are particularly vulnerable and are selectively obliterated upon withdrawal of VEGF. The plasticity window for vessel regression is determined by a delay in the recruitment of periendothelial cells to the preformed endothelial plexus. Thus fine-tuning of microvascular density takes place mostly in the newly formed plexus, but the mature system is refractory to episodic changes in tissue oxygenation. These regulatory links may malfunction in certain pathological settings.
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PMID:Vascular endothelial growth factor and vascular adjustments to perturbations in oxygen homeostasis. 1135 Jul 31

Retinopathy of prematurity (ROP) is a major problem in both highly developed countries and countries with emerging technology. The incidence of ROP has been stable over the last 2 decades despite improvements in neonatology. Threshold ROP occurs in about 5% of premature infants in the US with birthweights <1.25kg. Despite treatment, a sizable minority will become blind (up to 20 to 30%). The pathophysiology of ROP can be separated into 2 phases. Phase I is hyperoxia-vasocessation. Phase II is hypoxia-vasoproliferation. The former occurs immediately following premature birth. The provision of supplemental oxygen causes retinal hyperoxia, a down regulation of vascular endothelial growth factor (VEGF) and a consequent cessation of normal retinal vascularisation. Systemic factors and increasing retinal metabolic demands cause a shift to phase II when a relative retinal hypoxia develops. This hypoxia stimulates VEGF production, leading to renewed vascularisation. This can be the resumption of normal vascularisation or abnormal neovascularisation, depending on local retinal responses. The management of ROP begins with a reliable evidence-based screening protocol. All interested parties must cooperate in developing and implementing foolproof screening protocols. Hospital officials, nursery personnel, neonatologists and ophthalmologists all have areas of responsibility in ensuring adequate screening. ROP management involves prevention, interdiction and correction. Prevention includes: adequate prenatal care which minimises premature birth, and appropriate systemic intensive care which lessens the tissue hyperoxia/hypoxia swings. Pharmacological vitamin E supplementation has largely been abandoned and ambient light reduction has been shown to be ineffective. The value of inositol supplementation and angiogenesis inhibitors in preventing ROP is presently under investigation. Interdiction concentrates on ablation of the peripheral avascular retina, thus dramatically decreasing VEGF production. Both cryotherapy and laser photocoagulation are effective; however, unfortunately, poor outcomes persist despite treatment. Supplemental oxygen administration has so far proven ineffective in limiting ROP progression. Finally, correction focuses on vitrectomy/retinal detachment repair. While anatomically successful, this procedure is often unsuccessful in terms of restoration of vision (<5% success rate). In conclusion, despite improvements in neonatology, ROP, potentially leading to blindness, continues to be a common problem associated with prematurity. Future management success must concentrate on discovering new modes of treatment, especially prevention.
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PMID:The management of retinopathy of prematurity. 1135 98

The requirement for the nonreceptor tyrosine kinase c-abl in the pathogenesis of retinopathy of prematurity (ROP) was examined using the mouse model for ROP and c-abl-deficient mice. Hyperoxia-induced retinal neovascularization was observed in wild-type and heterozygous mice but animals that were homozygous null for c-abl did not develop a vasoproliferative retinopathy in response to hyperoxia. Two gene products, endothelin-1 (ET-1) and vascular endothelial growth factor (VEGF), have been implicated in the pathogenesis of ROP. The mRNA expression of ET-1 and VEGF was assessed in mice maintained in normoxia and in hyperoxia-exposed mice. ET-1 mRNA levels were unchanged in wild-type mice throughout the hyperoxia treatment, suggesting that ET-1 mRNA expression is not regulated by the increase in inspired oxygen. In wild-type mice maintained in room air, VEGF mRNA levels rose threefold from postnatal day 6 (P6) to P17. When wild-type mice were treated with the hyperoxia regimen, a fivefold decrease in VEGF mRNA expression was observed from P7 to P16. However, retinal VEGF expression in hyperoxia-treated homozygous null mice did not decrease and remained at control levels. These data suggest that c-abl is required for the hyperoxia-induced retinal neovascularization and hyperoxia-induced decrease in VEGF mRNA levels.
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PMID:c-abl is required for the development of hyperoxia-induced retinopathy. 1141 93

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