Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

One of the key molecules promoting angiogenesis is the endothelial cell-specific mitogen, vascular endothelial growth factor (VEGF or VEGF-A), which acts through two high-affinity receptor tyrosine kinases (VEGFR), VEGFR-1 (or Flt-1) and VEGFR-2 (or KDR/Flk-1). It was shown before that a soluble variant of VEGFR-1 (sVEGFR-1) can be generated by differential splicing of the flt-1 mRNA. This soluble receptor is an antagonist to VEGF action, reducing the level of free, active VEGF-A, and therefore, plays a pivotal role in the generation of vascular diseases like pre-eclampsia or intra-uterine growth retardation. Here we show that sVEGFR-1 is produced by cultured human microvascular and macrovascular endothelial cells and a human melanoma cell line. The soluble receptor is mainly complexed with ligands; only 5-10% remains detectable as free, uncomplexed receptor protein. Furthermore, we show the time course of total and free sVEGFR-1 release together with its putative ligands, VEGF-A and placenta growth factor (PIGF), from macrovascular endothelial cells. The release of sVEGFR-1 was quantitatively measured in two different ELISA types. The release of sVEGFR-1 was strongly enhanced by phorbol-ester (PMA); the cells produced up to 22 ng/ml of sVEGFR-1 after 48 hours. The expression of VEGF-A and PIGF was moderately influenced by PMA. We also show a hypoxia-induced increase of sVEGFR-1 expression in cells cultured from placenta, a tissue that has a high flt-1 gene expression. Moreover, we demonstrate that sVEGFR-1 in amniotic fluids acts as a sink for exogenous VEGF165 and PIGF-2. Here, for the first time, to what extent recombinant ligands have to be added to compensate for the sink function of amniotic fluids was analyzed. In conclusion, human endothelial cells produce high levels of sVEGFR-1, which influences the availability of VEGF-A or related ligands. Therefore, sVEGFR-1 may reduce the ligand binding to transmembrane receptors and interfere with their signal transduction.
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PMID:Release and complex formation of soluble VEGFR-1 from endothelial cells and biological fluids. 1078 Jun 61

Vascular endothelial growth factor (VEGF) intracellular signaling in endothelial cells is initiated by the activation of distinct tyrosine kinase receptors, VEGFR1 (Flt-1) and VEGFR2 (Flk-1/KDR). Because the tyrosine kinase-dependent transcription factors known as STAT (signal transducers and activators of transcription) proteins are important modulators of cell growth responses induced by other growth factor receptors, we have determined the effects VEGF of on STAT activation in BAEC (bovine aortic endothelial cells). Here, we show that VEGF induces tyrosine phosphorylation and nuclear translocation of STAT1 and STAT6. VEGF also stimulates STAT3 tyrosine phosphorylation, but nuclear translocation does not occur. We found that placenta growth factor, which selectively activates VEGFR1, has no effect on the STATs. However, upon VEGF stimulation, STAT1 associates with the VEGFR2 in a tyrosine kinase-dependent manner, indicating that VEGF-induced STAT1 activation is mediated primarily by VEGFR2. Thus, our study shows for the first time that VEGF activates the STAT pathway through VEGFR2. Because the growth-promoting activity of VEGF depends upon VEGFR2 activation, these findings suggest a role for the STATs in the regulation of gene expression associated with the angiogenic effects of VEGF.
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PMID:Vascular endothelial growth factor activates STAT proteins in aortic endothelial cells. 1096 83

Vascular endothelial growth factor (VEGF) and tumor necrosis factor-alpha (TNF-alpha) have been shown to synergistically increase tissue factor (TF) expression in endothelial cells; however, the role of the VEGF receptors (KDR, Flt-1, and neuropilin) in this process is unclear. Here we report that VEGF binding to the KDR receptor is necessary and sufficient for the potentiation of TNF-induced TF expression in human umbilical vein endothelial cells. TF expression was evaluated by Western blot analysis and fluorescence-activated cell sorting. In the absence of TNF-alpha, wild-type VEGF- or KDR receptor-selective variants induced an approximate 7-fold increase in total TF expression. Treatment with TNF alone produced an approximate 110-fold increase in total TF expression, whereas coincubation of TNF-alpha with wild-type VEGF- or KDR-selective variants resulted in an approximate 250-fold increase in TF expression. VEGF lacking the heparin binding domain was also able to potentiate TF expression, indicating that heparin-sulfate proteoglycan or neuropilin binding is not required for TF up-regulation. Neither placental growth factor nor an Flt-1-selective variant was capable of inducing TF expression in the presence or absence of TNF. Inhibition of protein-tyrosine kinase or protein kinase C activity significantly blocked the TNF/VEGF potentiation of TF up-regulation, whereas phorbol 12-myristate 13-acetate, a protein kinase C activator, increased TF expression. These data demonstrate that KDR receptor signaling governs both VEGF-induced TF expression and the potentiation of TNF-induced up-regulation of TF.
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PMID:Vascular endothelial growth factor KDR receptor signaling potentiates tumor necrosis factor-induced tissue factor expression in endothelial cells. 1105 94

The angiogenic endothelium of the chorioallantoic membrane (CAM) offers minimal restriction to macromolecular efflux at Day 4.5 of the normal 21-day chick gestation. Vascular endothelial growth factor (VEGF)-specific Flk-1 and Flt-1 tyrosine phosphorylation was observed at Day 4.5 by receptor immunoprecipitation and requisite immunoblotting. Further, general inhibition of tyrosine phosphorylation by either genistein or tyrphostin (10(-4) M) served to reduce FITC-Dextran 40 extravasation at Day 4.5. Likewise, anti-VEGF, but not anti-FGF-2 mAb, abolished the temporal endothelial hyperpermeability. These results are consistent with the established permeability-enhancing function of VEGF. Normal differentiation of the restrictive CAM endothelial barrier at Day 5. 0 was associated with reduced Flk-1 and Flt-1 expression, but sustained tyrosine phosphorylation of the residual RTKs. Moreover, inhibition of VEGF/RTK activity by anti-VEGF mAb at Day 5.0 did not enhance normal endothelial barrier function. Likewise, neither VEGF (5 x 10(-4) to 10(-15) M) nor PlGF (10(-6) to 10(-8) M), which selectively binds Flt-1, served to increase FITC-Dextran 40 efflux at Day 5.0. Together, these results are consistent with the suggestion that down-regulation of the permeability-related VEGF signal correlates temporally with the ontogeny of restrictive endothelial barrier function during angiogenesis in vivo.
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PMID:Vascular endothelial growth factor fails to acutely modulate endothelial permeability during early angiogenesis in the chick chorioallantoic membrane. 1107 37

The vascular endothelial growth factor is produced by a large variety of human tumors, including melanoma, in which it appears to play an important role in the process of tumor-induced angiogenesis. Little information is available on the role of placenta growth factor, a member of the vascular endothelial growth factor family of cytokines, in tumor angiogenesis, even though placenta growth factor/vascular endothelial growth factor heterodimers have been recently isolated from tumor cells. To investigate the role of placenta growth factor and vascular endothelial growth factor homodimers and heterodimers in melanoma angiogenesis and growth, 19 human melanoma cell lines derived from primary or metastatic tumors were characterized for the expression of these cytokines and their receptors. Release of placenta growth factor and vascular endothelial growth factor polypeptides into the supernatant of human melanoma cells was demonstrated. Reverse transcriptase polymerase chain reaction analysis showed the presence of mRNAs encoding at least three different vascular endothelial growth factor isoforms (VEGF(121), VEGF(165), and VEGF(189)) and transcripts for two placenta growth factor isoforms (PlGF-1 and PlGF-2) in human melanoma cells. In addition, placenta growth factor expression in human melanoma in vivo was detected by immunohistochemical staining of tumor specimens. Both primary and metastatic melanoma cells were found to express the mRNAs encoding for vascular endothelial growth factor and placenta growth factor receptors (KDR, Flt-1, neuropilin-1, and neuropilin-2), and exposure of melanoma cells to these cytokines resulted in a specific proliferative response, supporting the hypothesis of a role of these angiogenic factors in melanoma growth. J Invest Dermatol 115:1000-1007 2000
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PMID:Human melanoma cells secrete and respond to placenta growth factor and vascular endothelial growth factor. 1112 Nov 33

Extensive angiogenesis and invasion of the maternal decidua by trophoblasts are essential for the development and function of the placenta. Vascular endothelial growth factors (VEGF), placenta growth factor (PlGF) and their receptors VEGFR-1/Flt-1, VEGFR-2/KDR and VEGFR-3/Flt4 have important roles in vasculogenesis and angiogenesis. We have studied the localization of these proteins by immunohistochemistry and Western blotting in the placenta and of PlGF in maternal serum, and their association with diabetes, pre-eclampsia, fetal growth restriction (FGR) and fetal alcohol syndrome (FAS). VEGFR-1 and VEGFR-3 were detected mainly in the syncytiotrophoblastic layer whereas VEGFR-2 was detected in the vascular endothelial cells of the placenta. VEGFR-1, but not the other receptors, showed increased expression in placental syncytiotrophoblasts from 50% of patients with severe pre-eclampsia and FGR when compared with normal placentas. PlGF was undetectable in 38 of 44 samples of amniotic fluid of mothers with normal and complicated pregnancies. However, maternal serum PlGF concentrations were significantly lower in pre-eclamptic patients and in those with FGR when compared to diabetic women or healthy controls. These results suggest that low maternal serum PlGF and increased placental expression of its receptor VEGFR-1 are associated with pre-eclampsia and FGR.
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PMID:Expression of vascular endothelial growth factor receptors 1, 2 and 3 in placentas from normal and complicated pregnancies. 1116 Aug 48

Vascular endothelial growth factor (VEGF) and its two receptors, Fms-like tyrosine kinase 1 (Flt-1) (VEGFR-1) and KDR/Flk-1 (VEGFR-2), have been demonstrated to be an essential regulatory system for blood vessel formation in mammals. KDR is a major positive signal transducer for angiogenesis through its strong tyrosine kinase activity. Flt-1 has a unique biochemical activity, 10-fold higher affinity to VEGF, whereas much weaker tyrosine kinase activity compared with KDR. Recently, we and others have shown that Flt-1 has a negative regulatory function for physiological angiogenesis in the embryo, possibly with its strong VEGF-trapping activity. However, it is still open to question whether the tyrosine kinase of Flt-1 has any positive role in angiogenesis at adult stages. In this study, we examined whether Flt-1+ could be a positive signal transducer under certain pathological conditions, such as angiogenesis with tumors overexpressing a Flt-1-specific, VEGF-related ligand. Our results show clearly that murine Lewis lung carcinoma cells overexpressing placenta growth factor-2, an Flt-1-specific ligand, grew in wild-type mice much faster than in Flt-1 tyrosine kinase domain-deficient mice. Blood vessel formation in tumor tissue was higher in wild-type mice than in Flt-1 tyrosine kinase-deficient mice. On the other hand, the same carcinoma cells overexpressing VEGF showed no clear difference in the tumor growth rate between these two genotypes of mice. These results indicate that Flt-1 is a positive regulator using its tyrosine kinase under pathological conditions when the Flt-1-specific ligand is abnormally highly expressed. Thus, Flt-1 has a dual function in angiogenesis, acting in a positive or negative manner in different biological conditions.
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PMID:Involvement of Flt-1 tyrosine kinase (vascular endothelial growth factor receptor-1) in pathological angiogenesis. 1122 52

1. The purpose of this study in the hamster cheek pouch was to determine whether or not vascular endothelial growth factor (VEGF) induced changes in plasma extravasation and if so, the mechanism(s) involved. 2. The cheek pouch microcirculatory bed of the anaesthetized hamster was directly observed under microscope and the number of vascular leakage sites, as shown by fluorescein isothiocyanate (FITC-dextran, 150 kD) extravasation, was counted. Drugs and VEGF were applied topically. VEGF from 0.05 to 0.5 microg ml(-1) (1.2 to 12 nM) produced a dose-dependent increase in the number of microvascular leakage sites from virtually none in basal conditions to up to 250 in some pouches. The effects of VEGF (0.1 microg ml(-1) or 2.4 nM) were blocked in a concentration-dependent manner by the non-specific heparin growth factor antagonist TBC-1635 (0.1, 1 and 3microM). The placenta growth factor (PlGF-1: 0.1 and 0.5 microg ml(-1) or 3.4 and 17 nM) did not increase plasma extravasation, per se, but abolished the effects of VEGF (2.4 nM). 3. The increases in microvascular leakage produced by VEGF (2.4 nM) were partially but significantly (P<0.05) inhibited by genistein (5 and 10 microM, up to 33% inhibition), LY 294002 (30 microM, 41%), bisindolylmaleimide (1 microM, 65%) and virtually abolished by indomethacin (3 microM, 88%) and L-nitro-arginine (10 microM, 95%), these drugs being inhibitors of tyrosine kinase, phosphatidylinositol-3-kinase, protein kinase C, cyclo-oxygenase and nitric oxide synthase respectively. None of these inhibitors, at the concentration tested, induced alone an increase in plasma extravasation. 4. These results indicate that the VEGF-induced plasma extravasation may involve the stimulation of VEGF-R2 (Flk-1/KDR) and the activation of phosphatidylinositol-3-kinase and protein kinase C. The production of both nitric oxide and prostaglandin is required to observe an increase in vascular leakage.
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PMID:Vascular endothelial growth factor and the in vivo increase in plasma extravasation in the hamster cheek pouch. 1125 Aug 86

Vascular endothelial growth factors (VEGFs) are known to increase vascular permeability. VEGF-A acts on two receptor tyrosine kinases, VEGF receptor-1 (VEGF-R1 or flt-1) and VEGF receptor-2 (VEGF-R2, flk-1 or KDR). VEGF-C acts only on VEGF-R2 on vascular endothelial cells, whereas placental growth factor-1 (PlGF-1) acts only on VEGF-R1. The effects of perfusion of these receptor-specific proteins on hydraulic conductivity (L(p)) was measured in frog mesenteric capillaries. The effect of PlGF on L(p) was not conclusive, and overall fluid flux did not increase during that time. VEGF-C acutely and transiently increased L(p) (4.5 +/- 0.9-fold), which was more obvious in a subset of vessels, in a similar manner to that reported for VEGF-A. In the subset of vessels in which VEGF-C significantly increased L(p) acutely, there was a sustained 12-fold increase in L(p) 20 min after perfusion, but this was not seen in those vessels which did not respond acutely to VEGF-C, or in vessels exposed to PlGF-1. L(p) was also increased 24 h after perfusion with VEGF-C, but not with PlGF-1. Western blot analysis showed that VEGF-R1 and VEGF-R2 are both present in frog tissue. These data show that the VEGFs that stimulate VEGF-R2 chronically increase L(p), but not those that stimulate VEGF-R1 only. This supports the hypothesis that chronic increases in microvascular permeability induced by VEGF are mediated via activation of VEGF-R2 rather than VEGF-R1.
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PMID:Differential effects of vascular endothelial growth factor-C and placental growth factor-1 on the hydraulic conductivity of frog mesenteric capillaries. 1131 53

Although the accumulation of vascular endothelial growth factor (VEGF) has been observed in human atherosclerotic lesions, the exact role of this growth factor in atherogenesis remains unknown. We hypothesized that VEGF in the vascular wall might have a preventive effect on endothelial cell damage during atherosclerosis. To test our hypothesis, we examined whether VEGF protects against the toxicity of oxidized low density lipoprotein (Ox-LDL) in cultured endothelial cells derived from bovine aortas (BAECs). Preincubation of BAECs with VEGF prevented Ox-LDL-induced toxicity in a preincubation time- and VEGF concentration-dependent manner. Addition of N(omega)-nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor, did not reverse the protective effect of VEGF on Ox-LDL toxicity. Incubation of BAECs with VEGF increased intracellular glutathione (GSH) content in a time-dependent manner. Combined addition of VEGF and L-buthionine sulfoximine, a GSH synthesis inhibitor, reversed both GSH levels and the protective effect of VEGF on Ox-LDL-induced cytotoxicity. Placenta growth factor, which ligates to the VEGF Flt-1 receptor but not KDR/Flk-1, failed to prevent Ox-LDL toxicity and had no effect on intracellular GSH levels. An anti-KDR antibody completely blocked these beneficial activities of VEGF. These results suggest that VEGF prevents Ox-LDL-induced endothelial cell damage via an intracellular GSH-dependent mechanism through the KDR/Flk-1 receptor.
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PMID:VEGF protects against oxidized LDL toxicity to endothelial cells by an intracellular glutathione-dependent mechanism through the KDR receptor. 1134 72


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