Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0242706 (hyperoxia)
 5,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study compared susceptibilities of Sprague Dawley (SD) and Brown Norway (BN) rats with ischemia-induced retinal neovascularization. An exposure to constant hyperoxia followed by normoxia induced significant retinal neovascularization in BN rats but not in SD rats, as demonstrated by fluorescein retinal angiography, measurement of avascular area, and count of preretinal vascular cells. These results indicate a rat strain difference in susceptibility to retinal neovascularization. To understand the molecular basis responsible for the strain difference, we have measured the levels of pigment epithelium-derived factor (PEDF), an angiogenic inhibitor, and vascular endothelial growth factor (VEGF), a major angiogenic stimulator in the retina. The hyperoxia-treated BN rats showed a significant reduction in retinal PEDF, but they showed a substantial increase of VEGF at both the protein and RNA levels, resulting in an increased VEGF-to-PEDF ratio. Hyperoxia-treated SD rats showed changes in PEDF and VEGF levels that were less in magnitude and of shorter duration than in BN rats. In age-matched normal BN and SD rats, however, there was no detectable difference in the basal VEGF-to-PEDF ratio between the strains. These observations support the idea that different regulation of angiogenic inhibitors and stimulators under ischemia are responsible for the differences in susceptibility to ischemia-induced retinal neovascularization in SD and BN rats.
 ...
PMID:Difference in ischemic regulation of vascular endothelial growth factor and pigment epithelium--derived factor in brown norway and sprague dawley rats contributing to different susceptibilities to retinal neovascularization. 1191 48

Normal pulmonary vascular development is the result of a complex interplay of growth factors, including vascular endothelial growth factor (VEGF) and the angiopoietins. Injury to the developing lung, whether due to hyperoxia or mechanical ventilation, results in disordered vascular development, ranging from an apparent arrest of microvascular development in milder injury to extensive microvascular derangement in more severe injury. Alterations in vascular growth factors may participate in these injuries. During injury to the developing animal lung, VEGF abundance is markedly decreased. In models of post-injury recovery, up-regulation of VEGF accompanies the re-establishment of normal vasculature. Alterations in lung VEGF levels in human premature infants are less clear cut. However, among humans premature newborns who later go on to develop bronchopulmonary dysplasia (BPD), VEGF production is decreased in comparison to those newborns who recover. Other angiogenic factors, such as the CXC ELR+ chemokines, are also altered in injury to the developing lung, but their specific roles in vascular injury are less clear. Strategies that enhance microvascular integrity, whether through attenuating alterations in vascular growth factors or by other means, also improve the outcome of lung injury. Such therapies may eventually offer hope in human BPD.
 ...
PMID:The role of vascular growth factors in hyperoxia-induced injury to the developing lung. 1208 14

Pulmonary hyperoxic injury manifests as widespread alveolar-epithelial and microvascular endothelial cell necrosis, resolution of which requires angiogenesis. We investigated the hypothesis that inhaled nitric oxide (iNO) and hyperoxia each decreases lung vascular endothelial growth factor (VEGF) expression but increases endostatin and that concurrent administration of both gases will show a greater effect. Piglets were randomized to breathe for 5 d room air (RA); RA + NO (RA + 50 ppm NO), O(2) (hyperoxia, F(I)O(2) >0.96), O(2) + NO, or O(2) + NO + REC (O(2) + NO plus recovery in 50% O(2) for 72 h. After the piglets were killed, we measured lung capillary leak, VEGF mRNA, VEGF, and endostatin protein in homogenates, plasma, and lavage. VEGF mRNA decreased significantly with O(2) and O(2) + NO compared with breathing RA (p < or = 0.05). VEGF protein declined in the experimental groups with a significant reduction in the recovery group compared with the RA group (p < or = 0.05). Similar but more dramatic, endostatin declined in all groups relative to the RA group (p < 0.001). Lavage fluid VEGF protein and lung capillary leak rose significantly with O(2) and O(2) + NO compared with RA, but endostatin was unchanged. At 72 h of recovery from hyperoxia, VEGF mRNA and lavage fluid VEGF but not lung VEGF protein had normalized. Hyperoxia and iNO suppresses lung endostatin expression, but iNO unlike hyperoxia alone does not alter lung VEGF production. Hyperoxia paradoxically raises lavageable VEGF levels. This latter effect and that on VEGF mRNA level but not protein is abrogated by recovery in reduced F(I)O(2) for 72 h.
 ...
PMID:Endostatin and vascular endothelial cell growth factor (VEGF) in piglet lungs: effect of inhaled nitric oxide and hyperoxia. 1259 92

Ischemia is a major stimulus for angiogenesis, a biological response mechanism that describes the formation of new blood vessels from existing vessels. An ischemic cell communicates with endothelial cells by soluble factors such as VEGF (vascular endothelial growth factor) and its receptors. A major transcriptional factor for VEGF is HIF-1 (hypoxia inducible factor). Proliferation of endothelial cells alone does not result in stable vascular tubes, this is only achieved by recruiting additional cells such as pericytes. The stabilisation and destabilisation of vessels, which are important prerequisites for vascular growth, are in a dynamic equilibrium which can be modified by additional growth factors such as angiopoietins. In this review we discuss some of the molecular mechanisms leading from ischemia to proliferative retinopathy with a special focus on retinopathy of prematurity and the closely related mouse model of hyperoxia-induced retinopathy. This model is very useful when developing new antiangiogenic therapies based on the increasing understanding of the molecular pathogenesis of ischemic proliferative retinopathy.
 ...
PMID:[Angioproliferative retinal disease caused by ischemia]. 1274 2

Oxygen administration to immature neonates suppresses VEGF-A expression in the retina, resulting in the catastrophic vessel loss that initiates retinopathy of prematurity. To investigate the mechanisms responsible for survival of blood vessels in the developing retina, we characterized two VEGF-A receptors, VEGF receptor-1 (VEGFR-1, also known as Flt-1) and VEGF receptor-2 (VEGFR-2, also known as Flk-1). Surprisingly, these two VEGF-A receptors differed markedly during normal retinal development in mice. At 5 days postpartum (P5), VEGFR-1 protein was colocalized with retinal vessels, whereas VEGFR-2 was detected only in the neural retina. Real-time RT-PCR identified a 60-fold induction of VEGFR-1 mRNA in retina from P3 (early vascularization) to P26 (fully vascularized), and no significant change in VEGFR-2 mRNA expression. Placental growth factor-1 (PlGF-1), which exclusively binds VEGFR-1, decreased hyperoxia-induced retinal vaso-obliteration from 22.2% to 5.1%, whereas VEGF-E, which exclusively binds VEGFR-2, had no effect on blood vessel survival. Importantly, under the same conditions, PlGF-1 did not increase vasoproliferation during (a). normal vessel growth, (b). revascularization following hyperoxia-induced ischemia, or (c). the vasoproliferative phase, indicating a selective function supporting blood vessel survival. We conclude that VEGFR-1 is critical in maintaining the vasculature of the neonatal retina, and that activation of VEGFR-1 by PlGF-1 is a selective strategy for preventing oxygen-induced retinal ischemia without provoking retinal neovascularization.
 ...
PMID:Selective stimulation of VEGFR-1 prevents oxygen-induced retinal vascular degeneration in retinopathy of prematurity. 1284 56

In mice the retinal vasculature develops in the first postnatal week by spreading from the optic nerve head towards the retinal periphery. During this growth period, exposure to hyperoxia causes vaso-obliteration of capillaries in the retinal center but not in peripheral regions. High oxygen levels lead to downregulation of vascular endothelial growth factor (VEGF), an important survival factor for vascular endothelial cells, which could explain the vaso-obliteration caused by hyperoxia. However, it is not clear why only capillaries in the center of the retina are affected. We therefore investigated how capillary obliteration correlates with VEGF mRNA distribution by in situ hybridization in retinal whole mount preparations. In mouse pups reared under normoxic conditions VEGF mRNA was detectable across the entire vascular network but was virtually absent in the immediate vicinity of arteries. This was true along developing retinal arteries but also around the optic nerve head through which the entire arterial blood supply for the retinal and hyaloid vasculature passes. In these areas capillaries were absent, resulting in so-called capillary free zones. Exposure to hyperoxia caused an expansion of areas with low VEGF mRNA which correlated with capillary obliteration in these regions. Combined capillary obliteration around the optic nerve head and along retinal arteries lead to a large capillary free zone in the center of the retina. Thus, our observations suggest that hyperoxia affects the retinal vasculature by reducing VEGF mRNA levels near arteries and causing a widening of capillary free zones.
 ...
PMID:Role of arteries in oxygen induced vaso-obliteration. 1290 63

The development of the heart is closely linked to its temporally and spatially regulated vascularization. Hypoxia has been shown to stimulate myocardial capillary growth and improve myocardial perfusion during reperfusion in postnatal animals exposed to chronic or intermittent exposure to hypobaria. Vascular endothelial growth factor (VEGF) is up-regulated by hypoxia via HIF-1alpha, and these two molecules are colocalized with presumptive regions of hypoxia. VEGF up-regulation in embryonic and fetal hearts correlates with vascular tube formation which progresses from an epicardial to endocardial direction prior to the establishment of a functional coronary circulation. Our studies on explanted embryonic quail hearts indicate that vascular tube formation is enhanced by hypoxia (5-10% O2) and inhibited by hyperoxia. Three splice variants of VEGF (122, 126, 190) were found to increase and decrease with hypoxia and hyperoxia, respectively. While VEGF synthesis is stimulated by hypoxia, there are differences in the vascular patterning between exogenous VEGF-induced vascularization and that induced by hypoxia. Thus, other, yet to be identified, molecules are recruited by hypoxia. Acute hypoxia selectively enhances at least three splice variants of VEGF-A, and also selectively up-regulates VEGFR-1 (flt-1). However, we suggest that VEGF-B, a ligand for VEGFR-1 may contribute to embryonic myocardial vascularization, since we have shown that it plays a key role in this process under normoxic conditions. A second mechanism by which hypoxia may play a role in vascularization of the heart is via its vasodilatory effects, once the coronary circulation is functional. Increased blood flow serves as a mechanical (stretch) trigger for activation of VEGF and its receptors. In sum, there is evidence that a relative hypoxia provides both metabolic and mechanical stimuli for vascular growth in the developing heart.
 ...
PMID:Hypoxic induction of myocardial vascularization during development. 1471 19

The embryonic cardiac outflow myocardium originates from a secondary heart-forming field to connect the developing ventricles with the aortic sac. The outflow tract (OFT) subsequently undergoes complex remodeling in the transition of the embryo to a dual circulation. In avians, elimination of OFT cardiomyocytes by apoptosis (stages 25-32) precedes coronary vasculogenesis and is necessary for the shortening of the OFT and the posterior rotation of the aorta. We hypothesized that regional myocardial hypoxia triggers OFT remodeling. We used immunohistochemical detection of the nitroimidazole EF5, administered by intravascular infusion in ovo, as an indicator of relative tissue oxygen concentrations. EF5 binding was increased in the OFT myocardium relative to other myocardium during these stages (25-32) of OFT remodeling. The intensity of EF5 binding paralleled the prevalence of apoptosis in the OFT myocardium, which are first detected at stage 25, maximal at stage 30, and diminished by stage 32. Evidence of coincident hypoxia-dependent responses included the expression of the vascular endothelial growth factor (VEGF) receptor 2 by the OFT myocardium, the predominant expression of VEGF122 (diffusible) isoform in the OFT, and the recruitment of QH1-positive pro-endothelial cells to the OFT and vasculogenesis. Exposure of embryos to hyperoxia (95% O(2)/5% CO(2)) during this developmental window reduced the prevalence of cardiomyocyte apoptosis and attenuated the shortening and rotation of the OFT, resulting in double-outlet right ventricle morphology, similar to that observed when apoptosis is directly inhibited. These results suggest that regional myocardial hypoxia triggers cardiomyocyte apoptosis and remodeling of the OFT in the transition to a dual circulation, and that VEGF autocrine/paracrine signaling may regulate these processes.
 ...
PMID:Role of myocardial hypoxia in the remodeling of the embryonic avian cardiac outflow tract. 1501 95

We have shown that hyperoxia reduces brain damage in a rat model of hypoxia-ischemia. The purpose of this study was to examine the possibility of hyperoxia in inducing vision-threatening retinopathy. Two different experiments were conducted in this study. PART 1: seven-day-old rat pups were subjected to unilateral carotid artery ligation followed by 2 h of hypoxia (8% O2 at 37 degrees C). Pups were treated with 100% oxygen at 1 ATA, 1.5 ATA, and 3.0 ATA for a duration of 1 h. PART 2: Newborn rat pups were exposed to 100% oxygen at 1, 1.5, or 3.0 ATA for 1 h, the same treatment protocol used for brain protection after hypoxia-ischemia. Retinopathy was evaluated by the degree of neovascularization (measuring retinal vascular density), by the structural abnormalities (histology) in the retina, and by the expression of hypoxia-hyperoxia sensitive proteins including hypoxia-inducible factor-1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) at 24 h, 1, 2, and 10 weeks after hyperoxia exposure. Hyperoxic treatment at all pressures administered significantly reduced the hypoxia-ischemic-induced reduction in brain weight. Retinal vascular density measurements revealed no signs of neovascularization after hyperoxia exposure. There were also no abnormalities in the structure of the retina and no changes in the protein expression of HIF-1alpha and VEGF following hyperoxia exposure. Exposure to hyperoxia for 1 h at normobaric or hyperbaric pressures did not result in the structural changes or abnormal vascularization that is associated with retinopathy of prematurity, suggesting that hyperoxia is a safe treatment for hypoxic newborn infants.
 ...
PMID:Transient exposure of rat pups to hyperoxia at normobaric and hyperbaric pressures does not cause retinopathy of prematurity. 1529 45

Retinal capillary quiescence is regulated by a delicate balance between proangiogenic and anti-angiogenic factors. Pathological angiogenesis is the result of a shift in this balance towards proangiogenic influences. Pathological angiogenesis is produced in a rat model of oxygen-induced retinopathy (OIR) by exposing newborn rat pups to alternating periods of hyperoxia and hypoxia. Based upon previous work, two similar exposure paradigms were investigated and compared, exposure of rat pups to alternating periods of 45 and 12.5% oxygen, and to alternating periods of 40 and 15% oxygen. The resulting retinal pathology was assessed by measurement of retinal clock hours with pathological blood vessel growth and the percentage of the retina that is avascular. The 45 and 12.5% exposure produced significantly greater incidence and severity of pathology than the 40 and 15% protocol. To explain the difference in pathology between these two very similar exposure protocols, retinal levels of proangiogenic vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) and anti-angiogenic pigment epithelium-derived factor (PEDF) were measured by ELISA and western blot analysis at 0, 2, and 6 days post-exposure. In whole retinal lysates, there were no significant differences in VEGFR2 and PEDF levels. However, VEGF levels were approximately 48 and 78% higher on post-oxygen exposure day 0 and 2, respectively, in the group treated with alternating periods of 45 and 12.5% oxygen compared to the group treated with alternating periods of 40 and 15% oxygen. There was no significant difference in VEGF levels between these two groups on day 6 post-exposure. Therefore, the difference in pathology observed between these two experimental paradigms is associated with differences in whole retinal VEGF levels, but not changes in whole retinal VEGFR2 or PEDF levels. The results of this study suggest the existence of a threshold in the rat model of OIR, such that a small change in blood oxygen profile triggers a disproportionate increase in subsequent neovascularization, which is accompanied by more dramatic changes of retinal VEGF level than VEGFR2 or PEDF level. If a similar threshold exists for humans, it could explain why some oxygen-treated premature infants develop retinopathy and others do not, despite similar gestational ages, birth weights and clinical courses.
 ...
PMID:Variable oxygen and retinal VEGF levels: correlation with incidence and severity of pathology in a rat model of oxygen-induced retinopathy. 1550 Aug 21


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>