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Query: UNIPROT:P06889 (Mol)
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Signaling through the hypoxia inducible factor (HIF)-VEGF-VEGF receptor system (VEGF signaling system) leads to angiogenesis and epithelial cell proliferation and is a key mechanism regulating alveolarization in lungs of newborn rats. Hyperoxia exposure (>95% O2 days 4-14) arrests lung alveolarization and may do so through suppression of the VEGF signaling system. Lung tissue mRNA levels of HIF-2alpha and VEGF increased from days 4-14 in normoxic animals, but hyperoxia suppressed these increases. Levels of HIF-2alpha and VEGF mRNA were correlated in the air but not the O2-treated group, suggesting that the low levels of HIF-2alpha observed at high O2 concentrations are not stimulating VEGF expression. VEGF164 protein levels increased with developmental age, and with hyperoxia to day 9, but continuing hyperoxia decreased levels by day 12. VEGFR1 and VEGFR2 mRNA expression also increased in air-exposed animals, and these, too, were significantly decreased by hyperoxia by day 9 and day 12, respectively. Receptor protein levels did not increase with development; however, O2 did decrease protein to less than air values. Hyperoxic suppression of VEGF signaling from days 9-14 may be one mechanism by which alveolarization is arrested.
Am J Physiol Lung Cell Mol Physiol 2003 Jul
PMID:Effects of hyperoxia on VEGF, its receptors, and HIF-2alpha in the newborn rat lung. 1262 31

Vascular endothelial growth factor (VEGF), produced predominantly by endothelial cells, is involved in angiogenesis and mitogenesis. Myofibroblasts (myoFb) are phenotypically transformed fibroblast-like cells found at the site of myocardial infarction. Since myoFb play a role in tissue repair/remodeling at the site of infarction, and express endothelin and angiotensin II (AngII), it was interesting to investigate whether myoFb express VEGF and its receptors de novo, and if the expression is influenced by vasoactive peptides. Primary cultures of myoFb were isolated from 4-week-old adult rat heart infarct were used in this study. Semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR), utilizing primers designed to amplify known isoforms of VEGF revealed expression of two predominant forms, VEGF120 and VEGF164 and northern blot hybridization detected VEGF mRNA of 4.5 kb. VEGF actions are mediated via two major receptors, Flt-1 and KDR, and hence the expression of these receptors was investigated. Flt-1 and KDR expression in myoFb was detected by RT-PCR, RNA transcripts were confirmed by northern blot hybridization while western blot confirmed the presence of VEGF, Flt-1 and KDR proteins in myoFb. In this study AngII upregulated VEGF and Flt-1 expression in myoFb, but not KDR; this was mediated predominantly by AT1-receptor. We report for the first time that cardiac myoFb, isolated from the site of infarction express VEGF, its receptors, Flt-1 and KDR, with modulation of VEGF and Flt-1 expression by AngII. Thus, VEGF may contribute to tissue remodeling and angiogenesis at the site of infarction in an autocrine manner.
J Mol Cell Cardiol 2003 Mar
PMID:Cardiac myofibroblasts: a novel source of vascular endothelial growth factor (VEGF) and its receptors Flt-1 and KDR. 1267 42

Vascular endothelial growth factor (VEGF) is fundamental for development and maintenance of endometrial and placental vascular function during pregnancy. While there are a number of studies on VEGF in the human placenta, they are mostly restricted to late pregnancy. To further understand the role of VEGF in mediating angiogenesis during human early pregnancy, we employed a rhesus monkey early pregnancy model to study the temporal and spatial expression of VEGF and its receptors, fms-like tyrosine kinase (Flt)-1, and kinase-insert domain-containing receptor (KDR) mRNAs and proteins in the uteri on day 12, 18, and 26 of pregnancy using in situ hybridization, RT-PCR, and immunohistochemistry. VEGF mRNA had been identified in the luminal epithelium on day 12, in the glandular epithelium on day 12 and 18, and the highest expression was detected in the walls of some spiral arterioles adjacent to the implantation site on day 18, in the placental villi and in the fetal-maternal border on day 18 and 26. Besides, immunostaining of VEGF was detected in the placental villi and endometrial compartments including spiral arteries walls and the glandular epithelium. The localization of VEGF in the endothelium correlates with the presence of Flt-1 and KDR receptors on vascular structure. All the results above suggest that VEGF-VEGFR pairs were involved in the process of trophoblast invasion, maternal vascular transformation, and fetoplacental vascular differentiation and development during the rhesus monkey early pregnancy. Expression of VEGF, Flt-1, and KDR in the epithelial cells also hints some additionally functional roles of VEGF during early pregnancy.
Mol Reprod Dev 2003 Jun
PMID:Expression of vascular endothelial growth factor and its receptors in the rhesus monkey (Macaca mulatta) endometrium and placenta during early pregnancy. 1270 22

The molecular mechanisms mediating the cellular adaptations to exercise training in human skeletal muscle are very poorly understood. To investigate the effect of endurance training on the expression of various genes at the mRNA levels in human skeletal muscle, focusing on angiogeneic factors, antioxidant enzymes, and uncoupling proteins (UCPs), seven untrained male students underwent an intensive swimming training five times a week for 3 months and two male students an intensive running training, respectively. Muscle biopsies were taken before training and about 48 h after the last session. All the subjects markedly increased their maximal oxygen uptake levels due to training (P < 0.001), indicating an improvement in aerobic capacity. After training, there were significant (P < 0.04) decreases in the expression of mRNAs for heat shock protein 70, Cu,Zn-superoxide dismutase (Cu,Zn-SOD), and Mn-SOD but a significant (P < 0.02) increase in UCP2 mRNA expression, whereas no definite changes were observed in the levels of mRNAs for vascular endothelial growth factor (VEGF), basic fibroblast growth factor, hypoxia-inducible factor-1alpha (HIF1alpha), myoglobin, or UCP3. The changes in HIF1alpha mRNA expression correlated well with those in VEGF mRNA expression after training (r=0.875, P < 0.01), suggesting that HIF1alpha influences the training-induced VEGF gene expression or alternatively that VEGF and HIF1alpha expressions are coregulated at the transcriptional level in human skeletal muscle. Taken together, it is envisioned that cumulative effects of transient changes in transcription during recovery from successive bouts of exercise may represent the underlying kinetic basis for the cellular adaptations associated with endurance training.
Res Commun Mol Pathol Pharmacol 2002
PMID:Transcription regulation of gene expression in human skeletal muscle in response to endurance training. 1463 13

The pathogenesis of systemic sclerosis (SSc) is characterized by activation of the immune system, impaired angiogenesis, and activated dermal fibroblasts. The effects of the immunosuppressive agent bucillamine (SA 96) on fibroblasts and angiogenic factors have not been examined. SA 96, and particularly its metabolite SA 981, increased the levels of vascular endothelial growth factor (VEGF) mRNA and protein dose-dependently in dermal fibroblasts from patients with SSc and healthy control subjects without influencing cell viability. SSc fibroblast cultures showed consistently a higher inducibility of VEGF than cultures from healthy control subjects. Preincubation with the SP-1 inhibitor mithramycin as well as blockade of nuclear factor (NF)-kappaB signaling with pyrrolidine dithiocarbamate treatment and IkappaB transfection reduced significantly the transcription of VEGF, indicating that both transcription factors contribute to the activation of VEGF by SA 981. Specific binding of NF-kappaB protein to its binding site after treatment with SA 981 was confirmed by electrophoretic mobility shift assay. In contrast, SA 981 did not influence the stability of VEGF mRNA as analyzed with actinomycin D assays. The study provides evidence for a role of NF-kappaB in the transcriptional regulation of the VEGF gene. SA 96 might have positive aspects on the impaired angiogenesis in patients with SSc.
Mol Pharmacol 2004 Feb
PMID:Bucillamine induces the synthesis of vascular endothelial growth factor dose-dependently in systemic sclerosis fibroblasts via nuclear factor-kappaB and simian virus 40 promoter factor 1 pathways. 1474 81

Alveolar macrophages (AM) play a key role in clearing atmospheric particulates from the lung surface and stimulating epithelial cells to produce proinflammatory mediators. The present study examines the role of "acute response" cytokines TNF-alpha and IL-1 beta released by AM exposed to ambient particulate matter with a diameter of <10 microm (PM(10)) in amplifying the proinflammatory mediator expression by A549 cells and human bronchial epithelial cells (HBEC). The results showed that supernatants from human AM incubated 24 h with PM(10) (100 microg/ml) contained more TNF-alpha, IL-1 beta, granulocyte-macrophage colony stimulating factor, IL-6, and IL-8 than nonexposed AM supernatants. The 3-h treatment of A549 cells with PM(10)-exposed AM supernatants increased TNF-alpha, IL-1 beta, IL-8, regulated on activation normal T-cells expressed and secreted (RANTES), and leukemia inhibitory factor mRNA compared with the treatment with nonexposed AM supernatants and, compared with untreated A549 cells, additionally increased ICAM-1 and monocyte chemotactic protein-1 mRNA. Preincubating PM(10)-exposed AM supernatants with anti-IL-1 beta antibodies reduced all the above mediators as well as VEGF mRNA expression (P < 0.05), while anti-TNF-alpha antibodies were less effective (P > 0.05), and the combination of the two antibodies most effective. When HBEC were treated similarly, anti-TNF-alpha antibodies had the greatest effect. In A549 cells PM(10)-exposed AM supernatants increased NF-kappa B, activator protein (AP)-1 and specificity protein 1 binding, while anti-TNF-alpha and anti-IL-1 beta antibodies reduced NF-kappa B and AP-1 binding. We conclude that AM-derived TNF-alpha and IL-1 beta provide a major stimulus for the production of proinflammatory mediators by lung epithelial cells and that their relative importance may depend on the type of epithelial cell target.
Am J Physiol Lung Cell Mol Physiol 2004 Jul
PMID:Contribution of IL-1 beta and TNF-alpha to the initiation of the peripheral lung response to atmospheric particulates (PM10). 1500 25

Understanding the development and progression of oral cancer is critical in the quest for successful therapeutic intervention. The hypoxic microenvironment present in human oral tumor in vivo may actively influence tumor growth and neovascularization. This study correlates expression of both VEGF and HIF-1alpha in normal keratinocytes and oral cancer cell lines and determine whether hypoxia played a role in VEGF and HIF-1alpha regulation. Three human oral cancer cell lines and three normal keratinocytes were exposed to both normoxia and hypoxia culture conditions. Northern and Western blot analysis were used to assess VEGF and HIF-1alpha expression in the different culture conditions. ELISA assays were performed to measure VEGF production in the different cell lines tested. Hypoxia upregulated VEGF and HIF-1alpha expression on both normal and oral cancer cell lines, with a statistically significant difference between normal and oral cancer cell lines. Pattern of hypoxia-induced VEGF mRNA level tightly followed the HIF-1alpha mRNA expression in the cell lines tested. These results suggest that hypoxia regulates both VEGF and HIF-1alpha expression in head and neck carcinoma cell lines, thus establishing a biochemical pathway between tumor hypoxia and neoangiogenesis in these aggressive neoplasms.
Exp Mol Pathol 2004 Apr
PMID:Correlation between VEGF and HIF-1alpha expression in human oral squamous cell carcinoma. 1501 Feb 93

VEGF expressed in glomerular podocytes, is known to increase vascular permeability to macromolecules. Angiotensin II can stimulate the release of VEGF, and the protective effects of angiotensin II antagonist against diabetic glomerular injury suggest that the angiotensin II-induced VEGF is an important pathogenetic mechanism in the development of proteinuria during diabetic nephropathy although this mechanism is not fully understood. In this study, the changes of VEGF expression was examined in the experimental diabetic nephropathy to determine whether these changes were modified by renoprotective intervention by blockers of angiotensin II receptors. The streptozotocin- induced diabetic rats were treated with L-158,809, a blocker of angiotensin II receptors, for 12 weeks. Age-matched rats with L-158,809 served as controls. RT-PCR and immunohistochemistry were used to assess and quantify gene and protein expression of VEGF. A progressive increase in urinary protein excretion was observed in diabetic rats. Glomerular VEGF expression was significantly higher in diabetic rats than in the control groups, with a significant reduction in glomerular VEGF expression and proteinuria in L-158,809- treated diabetic rats. VEGF mRNA was also significantly higher in diabetic kidneys than in the control groups, with a significant reduction in VEGF mRNA in L-158,809-treated diabetic kidneys. These results demonstrates that VEGF expression is significantly increased in diabetic podocytes, and angiotensin II receptor antagonist attenuated these changes in VEGF expression and prevented the development of proteinuria in vivo. Attenuation of increased VEGF expression in podocytes could contribute to the renoprotective effects of angiotensin II receptor antagonists in diabetic nephropathy.
Exp Mol Med 2004 Feb 29
PMID:Angiotensin II receptor blocker attenuates overexpression of vascular endothelial growth factor in diabetic podocytes. 1503 73

To investigate the differential short-term effects of selective estrogen receptor (ER) modulators (SERMs) on uterus, we treated adult ovariectomized rats with a novel SERM, ospemifene (Osp), two previously established SERMs (tamoxifen and raloxifene (Ral)) and estradiol. The expression of two estrogen-regulated early response genes c-fos and vascular endothelial growth factor (VEGF), and DNA synthesis were analysed at 1-24 h after treatment of ovariectomized rats. Induction of c-fos mRNA by each of the SERMs showed a biphasic pattern with peaks at 3 and 20 h, respectively. The maximum level of VEGF mRNA was observed at 1 h after raloxifene and 6 h after tamoxifen or ospemifene treatment. Maximum levels of the c-fos and VEGF mRNA after raloxifene treatment were higher than those seen after treatments with E2 or a corresponding dose of tamoxifen or ospemifene. DNA synthesis was significantly increased by ospemifene, tamoxifen and raloxifene both in luminal and glandular epithelium. The stimulation was transient, peaking at 16 h. In comparison, the maximum level observed at 16 h after E2 treatment sustained at least until 24 h. DNA synthesis in stromal cells was increased by the SERMs but not by E2 at 24 h. When treated together with E2, the SERMs were able to antagonise E2-stimulated DNA synthesis at 16 h. Our results demonstrate that the initial response of uterus to ospemifene, raloxifene and tamoxifen includes activation of early response genes and even transient stimulation of DNA synthesis in spite of their different long-term effects. However, the early stimulatory events may be mediated by different mechanisms leading to diverging pathways in various tissue compartments and development of differential SERM-specific long-term responses of uterus.
J Steroid Biochem Mol Biol 2004 Feb
PMID:Comparative study of the short-term effects of a novel selective estrogen receptor modulator, ospemifene, and raloxifene and tamoxifen on rat uterus. 1508 46

We hypothesize that poly(ADP-ribose) polymerase (PARP) activation is an important mechanism in the oxidative stress-related development of diabetic retinopathy. In the experiments reported here, we evaluated if: a) PARP activation is present in the retina in short-term diabetes; and b) PARP inhibitors, 3-aminobenzamide and 1,5-isoquinolinediol, counteract diabetes- and hypoxia-induced retinal VEGF formation. In vivo studies were performed in control and streptozotocin-diabetic rats treated with/without 3-aminobenzamide or 1,5-isoquinolinediol (30 and 3 mg/kg per day, intraperitoneally, for 2 weeks after 2 weeks of diabetes). In vitro studies were performed in human retinal pigment epithelial cells exposed to normoxia or hypoxia with/without 3-aminobenzamide and 1,5-isoquinolinediol at 200 and 2 micro M. Retinal immunostaining for poly(ADP-ribose) was increased and NAD concentration reduced in diabetic rats, and both variables were corrected by PARP inhibitors. Retinal VEGF protein (ELISA, immunohistochemistry), but not mRNA (ribonuclease protection assay) abundance, was increased in diabetic rats, and this increase was corrected by both 3-aminobenzamide and 1,5-isoquinolinediol. PARP inhibitors did not affect retinal glucose, sorbitol pathway intermediates or lipid peroxidation in diabetic rats. Hypoxia caused a several-fold increase in both VEGF-mRNA and protein in retinal pigment epithelial cells. VEGF mRNA overexpression was only slighly blunted by PARP inhibitors whereas VEGF protein was corrected. In conclusion, PARP is involved in diabetes- and hypoxia-induced VEGF production at post-transcriptional level, downstream from the sorbitol pathway activation and oxidative stress. The results justify studies of PARP inhibitors in models of retinopathy of prematurity and diabetic retinopathy.
Int J Mol Med 2004 Jul
PMID:Poly(ADP-ribose) polymerase inhibitors counteract diabetes- and hypoxia-induced retinal vascular endothelial growth factor overexpression. 1520 16


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