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:2.7.7.6 (RNA polymerase)
34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen with potent angiogenic and vascular permeability-inducing properties, both of which may be important for the function of islets of Langerhans. In this study, we have examined the expression of VEGF and its tyrosine kinase receptors (flt and flk-1) in isolated rat islets of Langerhans in vitro. When analyzed by in situ hybridization, islet tissue showed a significant 4.6-fold increase in VEGF mRNA expression over time in culture from 0 to 7 days. Islet tissue exposed to hypoxic/anoxic conditions for a period of 8 hr showed a 3.7-fold increase in VEGF mRNA when analyzed by Northern blot hybridization. Reverse transcriptase-polymerase chain reaction revealed the presence of both flt and flk-1 in freshly isolated islets, and two VEGF isoforms, namely VEGF120 and VEGF164. Three rodent beta-cell lines derived from insulinomas (RINm5F-2A, INS-1, and MIN6) were also found to express VEGF by Northern blot hybridization. However, neither hypoxia/anoxia nor low (0.3 g/L)- or high (3.0 g/L)-glucose culture conditions modulated their expression of VEGF. VEGF derived from RINm5F-2A cells was bioactive in a three-dimensional in vitro model of angiogenesis, which assays for endothelial cell invasion and capillary morphogenesis. These findings demonstrate, first, that devascularization increases VEGF expression in isolated islet tissue, and they point to VEGF as a potentially important endogenous angiogenic stimulus for subsequent revascularization in vivo. Second, our observations raise the possibility that survival of transplanted islets may be improved by increasing VEGF expression before transplantation.
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PMID:Vascular endothelial growth factor is increased in devascularized rat islets of Langerhans in vitro. 903 36

The pituitary gland, a highly vascularised endocrine organ, contains permeable fenestrated endothelium that allows direct access of endocrine cells to the hemal milieu. Vascular endothelial growth factor (VEGF) has a mitogenic effect on endothelial cells and renders the endothelium more permeable. The following study investigated the expression of VEGF and its receptor flt-1 mRNA and protein in the pituitary gland of sheep. VEGF expression was localised, by in situ hybridisation and immunocytochemistry, mainly to the pars tuberalis/zona tuberalis (PT/ZT) region of the gland. No hybridisation signal was observed in the pars intermedia or pars nervosa. Reverse transcriptase-polymerase chain reaction (RT-PCR) Southern blotting confirmed the predominant expression of VEGF in the PT/ZT compared with the pars distalis (PD). Western blot analysis with the VEGF antibody revealed major (48 kDa) and minor (24 kDa) bands representing the monomer and dimer forms of VEGF and also confirmed the differential expression of VEGF in the PT/ZT compared with the PD. Double immunocytochemistry with VEGF and prolactin or luteinising hormone-beta (LH-beta) antibodies demonstrated that the VEGF-secreting cells are not lactotrophs or gonadotrophs. However, co-localisation of VEGF with S-100 was observed in a proportion of cells suggesting that some VEGF secreting cells are follicular stellate. Immunocytochemistry with a flt-1 antibody confirmed the expression of this high affinity receptor for VEGF in endothelial cells across the pituitary gland. Immunocytochemistry with the VEGF antibody using pituitary glands from intact and hypothalamo-pituitary disconnected sheep demonstrated comparable expression patterns suggesting that the regulation of blood flow and vascular permeability in the pituitary gland is under local regulation and is independent of hypothalamic input.
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PMID:Pattern and localisation of expression of vascular endothelial growth factor and its receptor flt-1 in the ovine pituitary gland: expression is independent of hypothalamic control. 942 52

Vascular endothelial growth factor (VEGF) expression and microvessel density were studied in cases of advanced epithelial ovarian carcinoma to evaluate their usefulness as prognostic variables. Tumor samples from 18 patients with advanced stage serous epithelial ovarian cancer were evaluated for VEGF expression by reverse-transcriptase polymerase chain reaction (RT-PCR) analysis. Immunohistochemical study of corresponding archival tissues with an antibody to von Willebrand factor (vWF; FVIII-RA) was used for tumor microvessel count determinations. The correlation of VEGF expression and mean microvessel counts was determined by an unpaired t-test. Survival analysis for known prognostic factors and VEGF expression was performed. Survival distributions were calculated by the product limit of Kaplan and Meier and significant differences between distributions were analyzed with a log rank test. From the RT-PCR analysis of tumor VEGF expression, 12 samples were found to be strongly positive, whereas six samples had low/negative VEGF expression. The median survival was 60 months for the VEGF-low/negative group and 28 months for the VEGF-positive group (P = 0.058). Other prognostic variables had minimal impact on survival, i.e. age < 65 years (P = 0.873), FIGO stage (P = 0.06), grade (P = 0.236) and debulking status (P = 0.842). Fourteen of 18 tumor specimens were suitable for microvessel counting. The mean microvessel counts of the VEGF-positive group and the VEGF-negative group were 27/hpf and 35/hpf, respectively (P = 0.16). In this preliminary analysis, high VEGF expression in epithelial ovarian carcinomas was associated with poor overall survival. Further study will be necessary to elucidate the lack of association of VEGF expression and tumor microvessel counts.
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PMID:Vascular endothelial growth factor (VEGF) expression and survival in human epithelial ovarian carcinomas. 957 Mar 55

Vascular endothelial growth factor (VEGF) is a potent inducer of angiogenesis and is constitutively expressed in the synovium of rheumatoid arthritis (RA). Over-expression of VEGF may play an important role in pathogenic vascularization and synovial hyperplasia of RA. In the present study, we examined whether disease-modifying anti-rheumatic drugs (DMARDs), including bucillamine (BUC), gold sodium thiomalate (GST), methotrexate (MTX) and salazosulfapiridine (SASP), act by inhibiting the production of VEGF by cultured synovial cells of patients with RA. Treatment of cultured synoviocytes with lipopolysaccharide (LPS) significantly increased VEGF production by cultured synovial cells. BUC significantly inhibited LPS-induced VEGF production, while GST tended to inhibit the production of VEGF. The inhibitory effects on VEGF production were dose-dependent. In contrast, MTX and SASP did not affect VEGF production. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis showed that BUC also inhibited LPS-induced VEGF mRNA expression in RA synovial cells. The present study provides the first evidence that BUC inhibits VEGF production and the expression of its mRNA in synovial cells of RA patients. Our results indicate that the anti-rheumatic effects of BUC are mediated by suppression of angiogenesis and synovial proliferation in the RA synovium through the inhibition of VEGF production by synovial cells.
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PMID:Inhibitory effects of anti-rheumatic drugs on vascular endothelial growth factor in cultured rheumatoid synovial cells. 1033 31

Angiogenesis is a complex process that includes recruitment and proliferation of mural cells-smooth muscle cells (SMC) and pericytes. Vascular endothelial growth factor (VEGF) has been shown to play an important role in angiogenesis and is an endothelial cell chemoattractant. In addition, certain VEGF isoforms have been implicated in the normal formation of smooth muscle cell-surrounded arteries. Because VEGF's role as a mural cell chemoattractant had not been explored, we examined the ability of VEGF to influence vascular SMC migration in vitro. A Boyden chamber migration assay demonstrated that VEGF (0-100 ng/ml) caused a dose-dependent migration of SMC. VEGF did not cause proliferation of SMC. Reverse transcriptase-polymerase chain reaction analysis demonstrated the presence of both KDR and flt mRNA, two known VEGF receptors, in SMC cultures. Western blot analysis of SMC lysates confirmed these data, revealing bands migrating at approximately 200 kDa and slightly below 200 kDa consistent with KDR and flt. These observations demonstrate that VEGF receptors are present on SMC, and that VEGF can act as an SMC chemoattractant.
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PMID:Vascular endothelial growth factor-induced migration of vascular smooth muscle cells in vitro. 1045 28

Vascular endothelial growth factor (VEGF) is a potent endothelial cell mitogen and angiogenic growth factor that enhances endothelial cell invasion through the extracellular matrix (ECM). While various cell types express VEGF receptors, little is known about the biological actions of VEGF on nonendothelial cells. Therefore, the main objective of the present study was to determine the effect of VEGF on the in vitro invasiveness and proliferation of human MDA-MB-231 breast carcinoma cells and human HTR-8/SVneo trophoblast cells. Reverse-transcriptase polymerase chain reaction analysis demonstrated the presence of transcripts encoding VEGF receptors (VEGFR) -1, -2, and -3 as well as neuropilins-1 and -2 in the trophoblast cells, and the presence of transcripts encoding VEGFR-2 and neuropilins-1 and -2 in the breast carcinoma cells. Both cell lines also expressed transcripts for VEGF-A, -B, -C and -D, as well as for placenta growth factor (PlGF). Although incubation with exogenous VEGF-A(165) or VEGF-A(121) did not affect the rate of proliferation of either the trophoblast or the breast carcinoma cells, incubation with these molecules reduced their ability to invade through reconstituted ECM (Matrigel). The effect of VEGF-A(165) on the invasiveness of both cell lines was inhibited by the inclusion of a neutralizing antibody to VEGF. Exogenous VEGF-A(165) also decreased the cell surface expression of the urokinase-type plasminogen activator (a molecule required for invasion) by the breast carcinoma and trophoblast cells. These results indicate that the biological actions of VEGF on certain cell types may differ from the effects of this molecule on vascular endothelial cells, and therefore are relevant to angiogenesis-based therapies.
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PMID:Inhibition of breast carcinoma and trophoblast cell invasiveness by vascular endothelial growth factor. 1258 44

Vascular endothelial growth factor (VEGF) carries out multifaceted functions in tumor development, and it exists as at least five isoforms with distinct biologic activities and clinical implications. Several strategies have been developed to block VEGF for cancer therapy; however, the approach to target-specific VEGF isoform(s) has not been explored to date. In the present study, we show that DNA vector-based RNA interference (RNAi), in which RNAi sequences targeting murine VEGF isoforms are inserted downstream of an RNA polymerase III promoter, has potential applications in isoform-specific "knock-down" of VEGF. Large molecular weight VEGF isoforms were specifically reduced in vitro in the presence of isoform-specific RNAi constructs. Additionally, H1 promoter may be superior to U6 promoter when used for vector-based RNAi of VEGF isoforms. This strategy provides a novel tool to study the function of various VEGF isoforms and may contribute to VEGF isoform-specific treatment in cancer.
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PMID:Vector-based RNAi, a novel tool for isoform-specific knock-down of VEGF and anti-angiogenesis gene therapy of cancer. 1268 59

Vascular endothelial growth factor (VEGF) and stem cell factor (SCF) act as growth factors for the hemangioblast, an embryonic progenitor of the hematopoietic and endothelial lineages. Because thrombopoietin (TPO) and its receptor, c-Mpl, regulate primitive hematopoietic populations, including bone marrow hematopoietic stem cells, we investigated whether TPO acts on the hemangioblasts that derive from differentiation of embryonic stem cells in vitro. Reverse transcriptase polymerase chain reaction analysis detected expression of c-Mpl beginning on day 3 of embryoid body differentiation when the hemangioblast first arises. In assays of the hemangioblast colony-forming cell (BL-CFC), TPO alone supported BL-CFC formation and nearly doubled the number of BL-CFC when added together with VEGF and SCF. When replated under the appropriate conditions, TPO-stimulated BL-CFC gave rise to secondary hematopoietic colonies, as well as endothelial cells, confirming their nature as hemangioblasts. Addition of a neutralizing anti-VEGF antibody did not block TPO enhancement of BL-CFC formation, suggesting that TPO acts independently of VEGF. These results establish that Mpl signaling plays a role in the earliest stages of hematopoietic development and that TPO represents a third growth factor influencing hemangioblast formation.
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PMID:A role for thrombopoietin in hemangioblast development. 1274 22

Vascular endothelial growth factor-A (VEGF-A) is an important mediator of angiogenesis in normal and neoplastic tissues. Total VEGF-A levels have been associated with melanoma progression, but the relative contributions of each isoform is unknown. To determine whether differences in the production of any or all of the major VEGF-A isoforms are related to stage of progression, we compared message levels for the three major isoforms of VEGF in melanoma specimens from different stages of progression.Primary melanomas (N = 18), primary recurrences (N = 5), regional dermal metastases (N = 11), nodal metastases (N = 12), normal lymph nodes (N = 18), and distant metastases (N = 9) were prospectively collected. Samples from the horizontal and vertical growth phases of primary tumors were also collected from five additional patients. Message levels for the three major VEGF-A isoforms were measured using real-time quantitative reverse-transcriptase polymerase chain reaction and normalized to beta-actin mRNA levels. There was a marked increase in the expression of all three VEGF-A isoforms from the vertical growth phase tissue as compared with the horizontal growth phase tissue. Primary tumors, local recurrences, regional dermal metastases, nodal metastases, and distant metastases all produced more VEGF(121) and VEGF(165) than negative nodes. Nodal metastases produced the highest level of these two isoforms, higher even than distant metastases. There was no significant difference in VEGF(189) message among the groups. Melanomas in the vertical growth phase produce more VEGF-A (all isoforms) than in the horizontal growth phase. Nodal metastases produce the highest levels of VEGF(121) and VEGF(165), but not VEGF(189) as compared with other stages of progression. These data suggest that the soluble forms of VEGF-A might be an important factor in melanoma metastasis to regional lymph nodes.
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PMID:Differential expression of vascular endothelial growth factor-A isoforms at different stages of melanoma progression. 1294 96

Angiogenesis or new vessel formation is an essential component in the growth and progression of neoplasms and there is growing evidence of its importance in hematological malignancies including multiple myeloma (MM). Vascular endothelial growth factor (VEGF) is believed to play a role in tumor angiogenesis. We studied the expression of VEGF and its receptors (VEGFR1 or Flt-1 and VEGFR2 or Flk-1/KDR) by myeloma cell lines and plasma cells isolated from patients, using different methods. VEGF expression by the plasma cells was demonstrated by immunohistochemistry in 18 of 20 patients with MM. Enzyme-linked immunosorbent assay demonstrated VEGF secretion in all six different myeloma cell lines studied. Five patient marrow samples and seven different myeloma cell lines were then studied for VEGF mRNA expression by reverse-transcriptase polymerase chain reaction (RT-PCR), which was positive in all. We further evaluated the expression of both VEGFR1 and VEGFR2 in different myeloma cell lines and five sorted myeloma bone marrow samples by RT-PCR. All the myeloma cell lines expressed VEGFR1 and three of the cell lines expressed VEGFR2. VEGFR1 expression was detected in all and VEGFR2 in all but one of the sorted marrow samples. Increased expression of VEGF by the myeloma cells taken in the context of the suspected prognostic value of marrow angiogenesis suggests a pathogenetic role for this cytokine and presence of its receptors on myeloma cells points toward an autocrine mechanism. Demonstration of the presence of VEGFR2 in our study provides a potential biological explanation for the preclinical activity observed with VEGFR2 inhibitors.
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PMID:Expression of VEGF and its receptors by myeloma cells. 1451 53


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