Role of Endogenous Vascular Endothelial Growth Factor in Tubular Cell Protection Against Acute Cyclosporine Toxicity1
Mar a Victoria Alvarez ArroyoYusuke SuzukiSusana Yag eCorina LorzSonsoles Jim nezCarlos SotoAntonio BaratEmilia BeldaFrancisco R. Gonz lez-PachecoJuan J. P. DeuderoMar a ngeles CastillaJes s EgidoAlberto OrtízCarlos Caramelo
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Abstract:
Background. Recent studies have shown that exogenous administration of vascular endothelial growth factor (VEGF) is protective against cyclosporine A (CsA) renal toxicity. No data are available, however, on the possible role of endogenous VEGF. Our objective was to examine whether endogenous VEGF has a significant role in the renal response against CsA toxicity. Methods. In vivo, we used high-dose (50–150 mg/kg/day) CsA ± specific goat anti-mouse VEGF blocking monoclonal antibody (α-VEGF) in mice. In vitro, we exposed mouse tubular cells (MCT) to CsA ± α-VEGF. Results. α-VEGF markedly enhanced CsA renal toxicity, inducing severe tubular damage and increased blood urea nitrogen. In animals treated with CsA + α-VEGF, damage progressed to generalized tubular injury (histology) and apoptosis (terminal deoxynucleotide transferase-mediated dUTP nick-end labeling) with associated anemia and reticulocytosis (18 days of treatment). CsA + α-VEGF treatments strikingly increased tubular VEGF and Bcl-xL proteins. In vitro, autocrine production of VEGF by MCT was identified by Western blot. Of specific interest, CsA toxicity in MCT increased significantly in the presence of α-VEGF. Conclusions. Endogenous VEGF has a relevant role in the renal tubular defense against CsA toxicity. Blockade of the VEGF effect by α-VEGF results in clear-cut intensification of the tubular injury and appearance of regenerative anemia in the CsA + α-VEGF–treated animals. The occurrence of both in vivo and in vitro effects of VEGF blockade provides evidence of a direct protective effect of VEGF on the tubular cell.Cite
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We have isolated and characterized a novel growth factor for endothelial cells, vascular endothelial growth factor B (VEGF-B), with structural similarities to vascular endothelial growth factor (VEGF) and placenta growth factor. VEGF-B was particularly abundant in heart and skeletal muscle and was coexpressed with VEGF in these and other tissues. VEGF-B formed cell-surface-associated disulfide-linked homodimers and heterodimerized with VEGF when coexpressed. Conditioned medium from transfected 293EBNA cells expressing VEGF-B stimulated DNA synthesis in endothelial cells. Our results suggest that VEGF-B has a role in angiogenesis and endothelial cell growth, particularly in muscle.
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This case—control study explored the relationship between early recurrent spontaneous abortion (RSA) and the expression of two genes: VEGFA, the gene encoding vascular endothelial growth factor (VEGF); and fms-related tyrosine kinase 1 (FLT1), the gene encoding the soluble VEGF receptor-1 (sFlt-1). Women experiencing RSA or undergoing induced abortions in the early stage of normal pregnancy were recruited to the study ( n = 30 per group). There were no significant between-group differences in maternal age or duration of pregnancy. The levels of VEGF and sFlt-1 mRNA in chorionic villus tissue samples were examined by quantitative reverse transcription—polymerase chain reaction. Levels of sFlt-1 and VEGF mRNA in the chorionic villus tissue of women with RSA were significantly higher than levels in the control group. This study demonstrated that there is a relationship between early RSA and VEGF and sFlt-1 levels, suggesting that overexpression of the FLT1 and VEGFA genes may be associated with the pathogenesis of RSA.
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Objective To determine the effect of PTK787 on the expression of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 mRNA,and further discuss the role of PTK787 on anti-acute myeloid leukemia.Methods The acute myeloid leukemia model was established on 40 severe combined immunodeficiency mice by HL-60 cells transplantation.The mice were divided into five group randomly,the normal group,the sicken group,the treated group with 50mg/kg PTK787,the treated group with 100mg/kg PTK787,the treated group with 200mg/kg PTK787.Logarithmic phase cells were implanted into the sicken group and the treated group by celiac injection.The expression of vascular endothelial growth factor was detected by enzyme linked immunosorbent assay.The expression of vascular endothelial growth factor receptor-2 mRNA was detected by reverse transcription-polymerase chain reaction.Results(1)Expression of vascular endothelial growth factors and vascular endothelial growth factor receptor-2 mRNA were determined on all mice.(2)Compared with the normal group,the mRNA level of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 in the sicken group was significantly and gradually increased with the course of disease.(3)Compared with the sicken group,the expression of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 mRNA of treated group decreased obviously.Conclusion The anti-effect on acute myeloid leukemia of PTK787 is related with the decrease expression of vascular endothelial growth factor and vascular endothelial growth factor receptor-2.
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Systemic vascular endothelial growth factor inhibition, in combination with chemotherapy, improves the outcome of patients with metastatic cancer. Peripheral sensory neuropathies occurring in patients receiving both drugs are attributed to the chemotherapy. Here, we provide unprecedented evidence that vascular endothelial growth factor receptor inhibitors trigger a painful neuropathy and aggravate paclitaxel-induced neuropathies in mice. By using transgenic mice with altered neuronal vascular endothelial growth factor receptor expression, systemic inhibition of vascular endothelial growth factor receptors was shown to interfere with the endogenous neuroprotective activities of vascular endothelial growth factor on sensory neurons. In vitro, vascular endothelial growth factor prevented primary dorsal root ganglion cultures from paclitaxel-induced neuronal stress and cell death by counteracting mitochondrial membrane potential decreases and normalizing hyperacetylation of α-tubulin. In contrast, vascular endothelial growth factor receptor inhibitors exerted opposite effects. Intriguingly, vascular endothelial growth factor or vascular endothelial growth factor receptor inhibitors exerted their effects through a mechanism whereby Hdac6, through Hsp90, controls vascular endothelial growth factor receptor-2-mediated expression of the anti-apoptotic Bcl2. Our observations that systemic anti-vascular endothelial growth factor therapies interfere with the neuroprotective activities of vascular endothelial growth factor may have important implications for the application of anti-vascular endothelial growth factor therapies in cancer patients.
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Objective:
To study the involvement of eight angiogenic growth factors that have been identified so far in the literature, especially vascular endothelial growth factor, in proliferative diabetic retinopathy.Methods:
Samples of neovascular membranes were obtained from diabetic patients; these samples, excised at vitrectomy, were used to study the expression of messenger RNA of the angiogenic factors by using the method of the reverse transcription-polymerase chain reaction. Vitreous aspirates that were taken from diabetic and control patients were used to quantify vascular endothelial growth factor-like activity with a competitive radioreceptor assay.Results:
Of the eight angiogenic factors studied, vascular endothelial growth factor was the only one that was always expressed in the samples of neovascular membranes. Furthermore, vascular endothelial growth factor receptor-binding activity was greater in vitreous aspirates that were obtained from diabetic patients than in samples that were taken from control patients (P<.01).Conclusion:
Vascular endothelial growth factor seems to be an appropriate candidate for mediating retinal diabetic neovascularization.Cite
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Angiogenesis is the formation of new blood vessels from the existing vasculature, and is essential for the growth and metastasis of most solid tumours. One of the most important growth factors involved in the angiogenesis process is vascular endothelial growth factor. Vascular endothelial growth factor expression has been shown to be regulated by female hormones in breast cancer cell lines, and two previous authors have reported on cyclical variations in serum vascular endothelial growth factor concentrations with conflicting results. No work has been performed on variations in plasma levels of vascular endothelial growth factor during the menstrual cycle. We therefore conducted the first prospective trial to compare serum and plasma levels of vascular endothelial growth factor in healthy pre-menopausal volunteers. Twenty healthy pre-menopausal women were recruited and had blood samples taken over one menstrual cycle with an average of eight samples taken per patient. Plasma and serum samples were then analysed for sex hormones and vascular endothelial growth factor 165. Serum vascular endothelial growth factor levels were found to be significantly higher than plasma vascular endothelial growth factor levels (P<0.005). We found no significant difference between serum and plasma vascular endothelial growth factor in the luteal and follicular phases of the cycle. The majority of the measurements for plasma levels of vascular endothelial growth factor at all phases of the cycle were under the limit of detection of the vascular endothelial growth factor ELISA kit. We found no significant correlation between plasma or serum levels of vascular endothelial growth factor and either FSH, LH, Oestradiol or Progesterone levels. This study has demonstrated no difference in serum concentrations of vascular endothelial growth factor during the different phases of the menstrual cycle in a group of healthy volunteers. We also demonstrated no obvious difference in plasma concentrations of vascular endothelial growth factor between the phases of the cycle, but most of the measurements were below the level of accuracy reported by the ELISA kit manufacturer. With the sensitivity of this ELISA test, therefore, we must still regard the question of whether there is a variation in plasma concentrations of vascular endothelial growth factor throughout the menstrual cycle as unanswered.
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To investigate the role of vascular endothelial growth factor-A (VEGF-A) isoforms in neovascular age-related macular degeneration.Choroidal neovascular membranes (CNV) were excised in 24 patients, 8 of them underwent previous photodynamic therapy. All procedures were performed before anti-VEGF therapies were implemented in Germany. Normal human donor eyes served as controls. Messenger RNA expression of total VEGF-A and VEGF-A isoforms was measured.Vascular endothelial growth factor-A121 is the most abundant isoform in CNV and control tissues. In controls, VEGF-A121 is lowest in neural retina and highest in choroids. For total VEGF-A and VEGF-A165, this is vice versa. VEGF-A165 and VEGF-A189 are significantly higher in CNV than in control choroids, the opposite is found for VEGF-A121. After photodynamic therapy, total VEGF-A and VEGF-A121 are increased, VEGF-A165 and VEGF-A189 are decreased. Age-dependently, there is an increase in VEGF-A165 and a decrease in VEGF-A121.Vascular endothelial growth factor-A isoforms are differentially distributed, suggesting that tissue-specific regulation of various isoforms is physiologically important. The disruption of this homeostasis in CNV membranes may be significant in the onset and progression of neovascular age-related macular degeneration. Our findings support the dominant role of VEGF-A121 in neovascular age-related macular degeneration but hint that VEGF-A165 may have an equivalent role in other neovascular retinal pathology.
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