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)

Destruction of pulmonary endothelial cells is characteristic of hyperoxic lung injury. During recovery from hyperoxia, pulmonary endothelial cells proliferate to regenerate the vascular endothelium. Vascular endothelial growth factor (VEGF) is a peptide growth factor that is mitogenic specifically for endothelial cells. We hypothesized that VEGF messenger RNA (mRNA) increases during recovery from acute hyperoxic lung injury. Adult rabbits were exposed to 100% oxygen for 64 h and allowed to recover in air for 0, 1, 3, and 5 days. In situ hybridization showed increased VEGF expression in alveolar epithelial cells beginning at 1 day recovery. By 3 days recovery the message was in alveolar epithelial cells throughout the lung. Compared with alveolar epithelial cells, little or no expression was noted in large vessel endothelial cells, airway cells, or smooth muscle cells. Combined in situ hybridization for VEGF and immunostaining for macrophages and other mesenchymal cells found no VEGF message in those cell types. Isolated alveolar macrophages had no detectable VEGF message. Cells expressing VEGF mRNA were enriched in alveolar type II cell preparations from recovering lung. Double in situ hybridization for VEGF and surfactant protein-C (SP-C) showed co-expression in a population of type II cells, but with an inverse relationship: cells with abundant VEGF mRNA did not have abundant SP-C mRNA. Type II cells in vitro expressed VEGF message, but only when the SP-C message abundance was relatively low. We conclude that alveolar type II cells express increased VEGF mRNA during recovery from acute hyperoxia. These findings are consistent with a role for VEGF in regulating microvascular endothelial repair after oxidant injury.
 ...
PMID:Vascular endothelial growth factor mRNA increases in alveolar epithelial cells during recovery from oxygen injury. 754 67

Normal neonatal lung growth requires a substantial increase in microvascular endothelial cells. Oxygen injury to neonatal lung destroys endothelial cells and alters the normal process of alveolarization, including development of the microvasculature. The mechanisms that regulate lung alveolar capillary growth and development are not known. Vascular endothelial growth factor (VEGF) is a specific mitogen for endothelial cells that is often expressed by epithelial cells in close proximity to capillary beds. VEGF expression is induced by hypoxia and may be inhibited by hyperoxia. We examined the cell-specific expression of VEGF during normal postnatal lung development and the effects of hyperoxic lung injury on VEGF mRNA and protein in vivo. Normal newborn rabbits between 1 day and 5 wk of age had VEGF transcripts located mainly in alveolar epithelial cells, with little or no VEGF mRNA noted in smooth muscle or endothelial cells. A subpopulation of freshly isolated, normal type II cells, but not mesenchymal cells, expressed VEGF mRNA. Newborn rabbits exposed to 100% oxygen for 4 days had no change in VEGF mRNA abundance, transcript location, or immunostaining. Animals exposed to 100% oxygen for an average of 9 days had an 80% decrease in lung VEGF mRNA abundance, decreased alveolar epithelial cell VEGF expression, and decreased VEGF immunostaining. Recovery of VEGF expression to control levels occurred during a 5-day recovery period. We conclude that alveolar epithelial cells in postnatal lung express VEGF, suggesting epithelial regulation of alveolar capillary formation. Furthermore, hyperoxic injury decreases neonatal lung VEGF mRNA and protein, which may be a contributory mechanism of impaired postnatal microvascular development in oxygen injury.
 ...
PMID:Hyperoxic injury decreases alveolar epithelial cell expression of vascular endothelial growth factor (VEGF) in neonatal rabbit lung. 916 Aug 38

Exposure to high levels of inspired oxygen leads to respiratory failure and death in many animal models. Endothelial cell death is an early finding, before the onset of respiratory failure. Vascular endothelial growth factor (VEGF) is highly expressed in the lungs of adult animals. In the present study, adult Sprague-Dawley rats were exposed to >95% FiO2 for 24 or 48 hours. Northern blot analysis revealed a marked reduction in VEGF mRNA abundance by 24 hours, which decreased to less than 50% of control by 48 hours. In situ hybridization revealed that VEGF was highly expressed in distal airway epithelial cells in controls but disappeared in the oxygen-exposed animals. Immunohistochemistry and Western blot analyses demonstrated that VEGF protein was decreased at 48 hours. TUNEL staining demonstrated the presence of apoptotic cells coincident with the decline in VEGF. Abundance of VEGF receptor mRNAs (Flt-1 and KDR/Flk) decreased in the late time points of the study (48 hours), possibly secondary to the loss of endothelial cells. We speculate that VEGF functions as a survival factor in the normal adult rat lung, and its loss during hyperoxia contributes to the pathophysiology of oxygen-induced lung damage.
 ...
PMID:Exposure to hyperoxia decreases the expression of vascular endothelial growth factor and its receptors in adult rat lungs. 1007 60

Lung development and repair of hyperoxic injury require closely regulated growth and regeneration of alveolar capillaries. Vascular endothelial growth factor (VEGF), a mitogen for endothelial cells, is expressed by alveolar epithelial cells. Alternative splicing of VEGF mRNA results in isoforms of varying mitogenicity and solubility. We examined changes in the proportions of the VEGF splice variant mRNAs in rabbit lung development and in control, oxygen-injured, and recovering newborn and adult rabbit lungs. The proportion of the 189-amino acid VEGF mRNA, which codes for an isoform that binds to the extracellular matrix, increased fivefold during development (from 8% of total VEGF message at 22 days gestation to 40% in 10-day newborn lungs; P < 0.001). During neonatal oxygen injury, its expression declined from 38 to 8% of VEGF message (P < 0.002) and returned to the control value in recovery. A similar pattern was observed in adults. VEGF protein in lung lavage fluid increased slightly during hyperoxia, declined to barely detectable levels at the 50% lethal dose time point, and increased 10-fold (newborn) or up to 40-fold (adult) in recovering animals. We conclude that alternative splicing may have important roles in the regulation of VEGF activity in developing and injured lungs.
 ...
PMID:Differential expression of VEGF mRNA splice variants in newborn and adult hyperoxic lung injury. 1033 42

Vascular insufficiency and retinal ischaemia precede many proliferative retinopathies and stimulate secretion of vasoactive growth factors. Vascular endothelial growth factor (VEGF) plays a major role and we therefore investigated the other members of the VEGF family: Placental growth factor (PlGF), VEGF-B, -C, and -D, and platelet derived growth factors (PDGF) A and B. Neonatal mice were exposed to hyperoxia for 5 days and then returned to room air (resulting in acute retinal ischaemia). RT-PCR demonstrated that all the members of the VEGF family are expressed in the retina and in situ hybridization (ISH) located their mRNAs primarily in ganglion cells. Similarly to VEGF itself, VEGF-C, PDGF-A, and PDGF-B were upregulated during retinal ischaemia (P < 0.05). Only PlGF gene expression increased during hyperoxia (P < 0.01). The expression pattern of these growth factors suggests a role in the normal retina and during vaso-obliterative and ischaemic phases.
 ...
PMID:Expression of the VEGF gene family during retinal vaso-obliteration and hypoxia. 1046 75

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

Vascular endothelial growth factor (VEGF) plays a central role in the development of ocular neovascularization (NV) and is an excellent target for therapeutic intervention. VEGF acts through several receptors, including VEGF receptor 1, VEGF receptor 2, neuropilin-1 (Npn1), and Npn2, but the exact role of these receptors in the development of retinal NV is unknown. In this study, we investigated the expression of npn2 mRNA during new blood vessel growth in the retina and used npn2 knockout mice to assess the impact of deficiency of Npn2 on retinal NV. The level of npn2 mRNA in the retina increased during retinal vascular development, after exposure to hyperoxia, and after the onset of retinal ischemia. Immunohistochemistry showed colocalization of Npn2 with a vascular marker in retinal NV. Compared with littermate controls, mice deficient in Npn2 had significantly less ischemia-induced retinal NV and very little subretinal NV due to expression of a Vegf transgene. These data suggest that Npn2 facilitates VEGF-induced retinal NV and may constitute a useful target for therapeutic intervention in ocular diseases complicated by NV.
 ...
PMID:Deficiency of neuropilin 2 suppresses VEGF-induced retinal neovascularization. 1550 78

Vascular endothelial growth factor (VEGF) is necessary for normal postnatal lung development and may underlie the structural lung damage that follows hyperoxic exposure. To determine the individual roles of VEGF receptors (VEGFR) 2 and 1 on postnatal lung growth, neonatal mice were treated with neutralizing antibodies to VEGFR-2 (DC101) or VEGFR-1 (MF1) in the perinatal period. At 1 wk of age, mice treated with DC101 on Days 2 and 4 of life had significantly larger mean alveolar diameters consistent with impaired alveolization. By 2 wk of age, however, perinatally treated DC101 mice had normal-appearing alveolar structure. Mice exposed to perinatal hyperoxia (O(2)) also had larger mean alveolar diameters at 1 wk of age, but unlike DC101-treated mice, their mitotic index was decreased at 1 wk of age and they had persistent alveolar enlargement beyond the first 2 wk of life. The O(2)-treated lung also had an increase in caspase 3 at 1 wk of age and significantly greater expression of nitrotyrosine at 2 wk of age. Therefore, VEGFR-2 blockade in the perinatal period disrupts early alveolar development, but the effect is reversible with time, whereas hyperoxic lung injury is associated with ongoing lung structural impairment.
 ...
PMID:Vascular endothelial growth factor receptor 2 blockade disrupts postnatal lung development. 1572 10

Prolonged exposure to hyperoxia results in hyperoxic acute lung injury (HALI). Vascular endothelial growth factor (VEGF) has been shown to have cytoprotective effects and prolong survival in an in vivo model of HALI. Heme oxygenase-1 (HO-1) has protective effects in hyperoxia; therefore, we hypothesized that induction of HO-1 would be an important contributor to VEGF-induced cytoprotection. Using inducible, lung-specific VEGF overexpressing transgenic mice, we demonstrated that VEGF is a potent inducer of HO-1 mRNA and protein in mouse lung. To evaluate the effect of inhibition of HO-1 on injury, VEGF transgenic mice were treated with HO-1 short interfering RNA (HO-1 siRNA) and exposed to hyperoxia. Total lung lavage protein concentration, TUNEL staining, lipid peroxidation, and wet-to-dry ratio were all increased, consistent with increased injury. These findings were corroborated by survival studies in which inhibition of HO-1 function using tin-protoporphryin or silencing of HO-1 with lentiviral HO-1 short hairpin RNA (ShRNA) significantly decreased survival in hyperoxia. We conclude from these data that VEGF-induced HO-1 is an important contributor to cytoprotection in this in vivo model of acute lung injury and that alterations in VEGF function in the lung are likely to be important determinants of the outcome of acute lung injury.
 ...
PMID:VEGF-induced heme oxygenase-1 confers cytoprotection from lethal hyperoxia in vivo. 1726 68

Vascular endothelial growth factor (VEGF) is a potent inflammation, vascular permeability, and angiogenic factor. Variations of the VEGF gene are implicated in the pathogenesis of diabetic retinopathy. Previous studies have shown that Brown Norway (BN) rats have higher retinal VEGF levels and more severe retinal vascular leakage than Sprague-Dawley (SD) rats in response to ischemia and diabetes. To investigate the molecular mechanism of vascular leakage in this animal model, F2 progeny were generated by crossbreeding BN and SD rats. Neonatal rats were exposed to hyperoxia to induce oxygen-induced retinopathy (OIR) models. The F2 rats in response to ischemia have shown a linear distribution of retinal VEGF levels, which is significantly and positively correlated to retinal vascular leakage. We identified a single nucleotide polymorphism (SNP) at upstream stimulating factor-binding site in the VEGF promoter region between BN and SD rats. No differences were found in retinal vascular permeability or VEGF levels between F2 rats with BN, SD, and BN/SD alleles of VEGF SNP. The increased retinal VEGF levels are correlated to ischemia-induced retinal vascular leakage in the OIR rat model. The VEGF mRNA and promoter are not responsible for increased retinal VEGF level and vascular permeability. The up-regulation of VEGF expression activated by a yet to be identified upstream factor or mediator affecting VEGF stability may be associated with a high susceptibility to retinal vascular leakage in BN rats.
 ...
PMID:Rat strain-dependent susceptibility to ischemia-induced retinopathy associated with retinal vascular endothelial growth factor regulation. 1744 32


1 2 Next >>