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:2.7.7.48 (transcriptase)
9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Formation of new blood vessels is essential for the process of wound and fracture healing. Little is known about the time-dependent expression and the involved splice variants of the vascular endothelial growth factor (VEGF). We therefore quantified and differentiated the angiogenic factor VEGF and its receptors (VEGFR) in a rat fracture model by immunohistochemical, biochemical and molecular biological methods. VEGF could be immunostained in chondrocytes and osteoblasts of the callus, but not in fibrous callus. In the capillaries, VEGFR-1 (flt-1) and VEGFR-2 (flk-1/KDR) were also visualized. Both receptors were also detectable in some chondrocytes and in osteoclasts. Enzyme-linked immunosorbent assay (ELISA) measurements showed high levels of VEGF in fractured tibiae and negligible ones in non-injured bone. Reverse transcriptase-polymerase chain reaction (RT-PCR) revealed expression of the rat splice variants VEGF(120) and VEGF(164) during the course of fracture healing, which corresponds to human VEGF121 and VEGF165 splice variants. VEGF plays the most important role during the early phase of fracture healing, but VEGF concentrations decrease further after day 5.
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PMID:Quantitative measurement of the splice variants 120 and 164 of the angiogenic peptide vascular endothelial growth factor in the time flow of fracture healing: a study in the rat. 1219 95

Angiogenesis is a critical step in tumor growth and metastatic invasion. We here report the study of the vascular status of 10 benign and 9 malignant pheochromocytomas. We examined the vascular architecture after immunostaining endothelial cells (CD34) and vascular smooth muscle cells (alpha-actin) and identified a vascular pattern characteristic of malignant lesions. To define a gene expression profile indicative of the invasive phenotype, we studied by in situ hybridization the expression of genes encoding several pro- and anti-angiogenic factors [hypoxia-inducible factor (HIF-1 alpha), EPAS1, vascular endothelial growth factor (VEGF), VEGF receptors, angiopoietins and their receptor Tie2, five genes of the endothelin system, and thrombospondin 1]. A semiquantitative evaluation of the labeling revealed an induction of genes encoding EPAS1, VEGF, VEGFR-1, VEGFR-2, endothelin receptor, type B (ETB) and endothelin receptor, type A (ETA) in malignant pheochromocytomas as compared to benign tumors. These differences were observed in tumor cells, in endothelial cells, or in both. Quantification by real-time reverse-transcriptase polymerase chain reaction showed an increase of EPAS1, VEGF, and ETB transcripts of 4.5-, 3.5-, and 10-fold, respectively, in malignant versus benign tumors. Furthermore, we observed a strong correlation between the expression of EPAS1 and VEGF in tumoral tissue and between EPAS1 and ETB in endothelial cells. Altogether, our observations show that analysis of angiogenesis provides promising new criteria for the diagnosis of malignant pheochromocytomas.
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PMID:Angiogenesis and vascular architecture in pheochromocytomas: distinctive traits in malignant tumors. 1236 97

To assess the possible involvement of vascular endothelial growth factor (VEGF) in the pathology of osteoarthritic (OA) cartilage, we examined the expression of VEGF isoforms and their receptors in the articular cartilage, and the effects of VEGF on the production of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in OA chondrocytes. Reverse transcriptase-polymerase chain reaction analyses demonstrated that mRNAs for three VEGF isoforms (VEGF(121), VEGF(165), and VEGF(189)) are detectable in all of the OA and normal (NOR) cartilage samples. However, the mRNA expression of their receptors (VEGFR-1 = Flt-1, VEGFR-2 = KDR and neuropilin-1) was recognized only in the OA samples. The protein expression of VEGFR-1 and VEGFR-2 in OA chondrocytes was also demonstrated by immunohistochemistry of the OA cartilage tissue and cultured OA chondrocytes. In situ hybridization and immunohistochemistry indicated that VEGF is expressed in the chondrocytes in the superficial and transitional zones of OA cartilage. A linear correlation was obtained between VEGF immunoreactivity and Mankin scores in the cartilage (r = 0.906, P < 0.001). The production levels of VEGF determined by enzyme-linked immunosorbent assay were significantly 3.3-fold higher in OA than in NOR samples (P < 0.001). Among MMP-1, -2, -3, -7, -8, -9, and -13, TIMP-1 and -2 measured by their sandwich enzyme immunoassay systems, the production of MMP-1 and MMP-3 but not TIMP-1 or TIMP-2 was significantly enhanced by the treatment of cultured OA chondrocytes with VEGF (P < 0.05), whereas no such effect was obtained with cultured NOR chondrocytes. These results demonstrate that VEGF and its receptors are expressed in OA cartilage, and suggest the possibility that VEGF is implicated for the destruction of OA articular cartilage through the increased production of MMPs.
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PMID:Vascular endothelial growth factor isoforms and their receptors are expressed in human osteoarthritic cartilage. 1250

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

Chronic decubital lesions have a limited potential to heal. Evidence suggests that a lack of local revascularization is involved in this aetiology. The present study investigated the expression of one of the most important angiogenic factors, the vascular endothelial growth factor (VEGF), in different regions of sacral chronic decubital lesions and in normal skin by immunohistochemical, biochemical, molecular, and cell biology methods. To elucidate some of the factors responsible for the induction of VEGF in chronic skin ulcers, cultured fibroblasts were exposed to hypoxia and/or growth factors. In the central part (zone I) of chronic ulcers and in normal skin, immunostaining for VEGF remained largely negative. However, VEGF could be immunostained in cells in the granulation tissue adjacent to central necrosis (zone II). VEGF receptor 2 (VEGFR-2; KDR) could also be identified in microvessels. High VEGF levels were present in homogenates from granulation tissue by enzyme-linked immunosorbent assay (ELISA) and western blot experiments: low concentrations were found in areas of central necrosis and negligible amounts were present in normal skin. Reverse transcriptase-polymerase chain reaction (RT-PCR) showed that only the splice variants VEGF(121) and VEGF(165) were expressed. In cultured fibroblasts, hypoxia or platelet-derived growth factor (PDGF) raised VEGF production. The angiogenic peptide VEGF is present in all zones of chronic decubital ulcers. Its strong expression within the adjacent granulation tissue supports the view that there is no deficiency of VEGF. VEGF may be involved in the healing process of chronic skin lesions, but it seems that loss of another factor may be responsible for the poor healing response.
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PMID:The angiogenic peptide vascular endothelial growth factor (VEGF) is expressed in chronic sacral pressure ulcers. 1269 51

Overexpression of vascular endothelial growth factor (VEGF) in the testis of transgenic mice induces infertility, suggesting a potential role for VEGF in the process of spermatogenesis. Spermatogenesis occurs within the confines of the seminiferous tubules, and the seminiferous epithelium lining these tubules consists of Sertoli cells and germ cells in various stages of maturation. We investigated the source of VEGF and VEGF-target cells within the seminiferous tubules of the normal mouse testis. Sections of testes fixed in Bouin solution and embedded in paraffin were subjected to immunofluorescent staining with specific antibodies against VEGF, and its receptors, VEGFR-1 (Flt-1) and VEGFR-2 (Flk-1). Total RNA was extracted from isolated populations of Sertoli cells, type A spermatogonia, pachytene spermatocytes, and spermatids. Primer pairs specific for VEGF and its receptors were designed and reverse-transcriptase polymerase chain reaction (RT-PCR) was performed. Immunofluorescent studies indicated that VEGF is strongly expressed in the cytoplasm of Sertoli cells. VEGFR-1 and VEGFR-2 were not expressed by the Sertoli cell. In contrast, a differential expression of VEGF receptors was observed in germ cells. Although VEGFR-2 was expressed in the cytoplasm of type A spermatogonia, VEGFR-1 was expressed in the acrosomal region of spermatids and spermatozoa. Pachytene spermatocytes did not exhibit any staining. Further, we examined the transcription of VEGF and its receptors by RT-PCR. VEGF was actively transcribed only in Sertoli cells. The transcription of VEGFR-2 was confined to type A spermatogonia. Interestingly, VEGFR-1 was transcribed both in pachytene spermatocytes and round spermatids. The mRNA expression of VEGFR-1 and VEGFR-2 in germ cells was inversely correlated during postnatal development of the mouse testis. Thus, VEGF may play a potential role in regulating the initial stages of the process of spermatogonial proliferation through VEGFR-2 and spermiogenesis through VEGFR-1.
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PMID:Expression of vascular endothelial growth factor receptors during male germ cell differentiation in the mouse. 1277 25

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

It is generally considered that genetic factors may contribute to the susceptibility of type 2 diabetic nephropathy. The purpose of the present study is to identify molecules that contribute to the development and/or progression of this disease. Differential display was performed to isolate genes in the kidney using the KK/Ta mouse model of type 2 diabetes. The differential expression of 8 randomly chosen candidate genes (DN1-8) were verified by reverse-transcriptase polymerase chain reaction (RT-PCR) or Northern blot analysis. DN1-3 (Zn-alpha2-glycoprotein, vascular endothelial growth factor receptor [VEGFR]-2, and lactate dehydrogenase [LDH]) were overexpressed and DN7-8 (peroxisome proliferator-activated receptor [PPAR]-interacting protein [PRIP], unknown) were underexpressed in the KK/Ta mouse kidney. DN4-6 (Ezrin, transcobalamin 2, aldo-ketoreductase) did not differ between KK/Ta and control (BALB/c) mice. DN8 only showed no significant sequence similarity to previously reported genes. Molecular cloning revealed that full-length DN8 shares 89% identity with human cholinephosphotransferase 1 (hCHPT1), and we designated it as "putative" mouse cholinephosphotransferase 1 (mCHPT1). The putative mCHPT1 gene was most closely mapped to the D10Mit94 locus with the highest logarithm of odds (lod) score. In situ hybridization revealed the levels of glomerular putative mCHPT1 in BALB/c mice tended to be slightly higher than those in KK/Ta mice. The altered renal mRNA expression of these genes may be involved in the development and/or progression of diabetic nephropathy.
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PMID:Altered mouse cholinephosphotransferase gene expression in kidneys of type 2 diabetic KK/TA mouse. 1525 74

Vascular endothelial growth factor (VEGF) is a dimeric heparin-binding glycoprotein that is a potent endothelial cell-specific mitogen with increased expression during adult cutaneous wound healing. VEGF activity is mediated by two receptors, VEGFR-1 (Flt-1) and VEGFR-2 (Flk-1/KDR), which are expressed primarily in vascular endothelial cells. Initiation of profibrotic cytokine expression likely coordinates the transition from scarless healing to scar formation in fetal wounds. Angiogenesis is an important component of the scarring repair process, but the function of VEGF and degree of angiogenesis during scarless repair has not been investigated. We hypothesize that VEGF and its receptors are differentially expressed in scarless compared with scarring fetal wounds because VEGF is implicated in angiogenesis during skin development and adult wound healing. Excisional wounds were created on fetal rats at gestational ages 16.5 days (E16) and 18.5 days (E18) (term = 21.5 days). Wounds were harvested at 24 and 72 hours (n = 12 wounds per time point). Nonwounded fetal skin (E17, E19, and E21) was used as control. Reduced-cycle, specific-primer, reverse-transcriptase polymerase chain reaction was performed to determine the expression of VEGF and its receptors, VEGFR-1 and VEGFR-2. Wounds at 72 hours and fetal skin controls were examined under high-power microscopy for blood vessel counts. Unpaired two-tailed t test was used (p < 0.05 was considered significant). VEGF expression increased 2.4-fold (p < 0.001) during normal skin development from E17 to E19. In scarless wounds (E16), VEGF expression increased 2.8-fold (p < 0.02) at 72 hours. No increased expression occurred in the scarring wounds (E18). VEGFR-1 and VEGFR-2 expression increased over 2-fold during normal skin development from E17 to E21. However, each was down-regulated 30 to 50 percent in scarless (E16) and scarring (E18) wounds. There is a 2-fold increase in mean vessel counts per high-power field in scarless (E16) wounds at 72 hours compared with age-matched control skin (p < 0.02) and a 1.7-fold increase in mean vessel count in scarring fetal wounds (E18) compared with age-matched control skin (p < 0.05). There is no difference in the total number of vessels found in scarless versus scarring wounds or between 19.5-day versus 21.5-day fetal skin. VEGF and its receptors, VEGFR-1 and VEGFR-2, increase expression during skin development and dermal differentiation. VEGF expression quickly elevates during scarless compared with scarring repair, which likely contributes to the more rapid scarless fetal repair rate. Similar numbers of new ves-sels are formed during scarless and scarring fetal repair.
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PMID:Increased angiogenesis and expression of vascular endothelial growth factor during scarless repair. 1562 52

Vascular endothelial growth factor (VEGF) is one of the key regulators of tumor neoangiogenesis. It acts through two types of high-affinity tyrosine kinase receptors (VEGF receptor-1 [VEGFR-1]/fms-related tyrosine kinase 1 [Flt-1] and VEGFR-2/kinase domain receptor [KDR]) expressed on endothelial cells. VEGFRs have also been detected on cancer cells, suggesting a possible autocrine effect of VEGF on their growth. We studied the expression of VEGF, VEGFR-1, and VEGFR-2 in human medulloblastoma cell lines (DAOY, D283Med, and D341Med) and investigated the possible autocrine mechanisms of VEGF on medulloblastoma cell proliferation. Reverse transcriptase PCR analysis showed the presence of VEGF and VEGFR mRNAs in all cell lines studied. Of the three VEGF isoforms, VEGF(121) and VEGF(189) were detected by Western blot analysis in all three medulloblastoma cell lines, whereas VEGF(165) was identified only in DAOY cells. Medulloblastoma cell lines expressed both VEGFR-1 and VEGFR-2. We also demonstrated expression of VEGF and its receptors in medulloblastoma tumor specimens. Exogenous VEGFR-2 inhibitor reduced the VEGF-dependent cell proliferation of DAOY and D283Med cells. In DAOY cells, VEGF(165) induced phosphorylation of VEGFR-2/KDR and of downstream proteins in the signal transduction pathway. These data suggest a possible autocrine role for VEGF in medulloblastoma growth. Targeting VEGF signaling may represent a new therapeutic option in the treatment of medulloblastoma.
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PMID:Functional VEGF and VEGF receptors are expressed in human medulloblastomas. 1770 59


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