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:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Expression of vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), and its receptors Flt-1 and KDR (Flk-1 in mouse) and their localization in the human testis were analyzed by means of reverse transcriptase-polymerase chain reaction (RT-PCR), Western blotting and immunohistochemistry. VEGF mRNA was detected in the human testicular tissue and in fragments of seminiferous tubules by means of RT-PCR, while fragments of blood vessels isolated from testes were negative. Western blotting procedure using a specific VEGF antibody, revealed two protein bands corresponding to 24 and 49 kDa in the extracts prepared from the whole testis and in the seminiferous tubules while no such bands were found in isolated fragments of human testicular blood vessels. Also immunohistochemically, human testicular blood vessels show no VEGF immunoreactivity, while Leydig cells and Sertoli cells were positive. The mRNA of the VEGF receptor Flt-1 was found to be expressed in human testicular tissue, in isolated fragments of testicular blood vessels and in seminiferous tubules as determined by RT-PCR procedure. In accordance with these results, the Flt-1 protein was immunohistochemically localized in Leydig, Sertoli and perivascular cells. Endothelial cells of certain segments of human testicular microvasculature also stained positive for Flt-1. Expression of VEGF receptor, KDR, could be demonstrated in human testicular tissue, in isolated seminiferous tubules and in isolated fragments of human testicular blood vessels by means of RT-PCR. Immunohistochemically, the KDR protein was localized in endothelial cells and perivascular cells of capillaries within the lamina propria of seminiferous tubules. Leydig cells and Sertoli cells show KDR immunoreactivity, too. Thus we demonstrate the presence of both types of VEGF receptors Flt-1 and KDR on Leydig as well as on Sertoli cells which are normal non-endothelial cells, suggesting hitherto unrecognized and novel functions for such receptors. The results obtained permit us to suggest VEGF as a paracrine mitogenic and angiogenic factor, responsible for modulating the capillarization of the human testicular tissue and maintaining the functions of testicular microvasculature. VEGF may also influence the permeability of capillaries passing through the groups of Leydig cells and those localized within the lamina propria of human seminiferous tubules. The differences in the expression pattern of the VEGF receptors in the human testicular tissue probably reflect different VEGF effects in different compartments of human testis.
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PMID:Vascular endothelial growth factor and its receptors in normal human testicular tissue. 925 59

Degradation of angiogenic mediators might be an underlying cause of chronic wounds. To test this hypothesis, we evaluated the expression and integrity of vascular endothelial growth factor, a potent angiogenic mediator, and its receptors, Flt-1 and KDR, in chronic venous leg ulcerations. Immunohisto- chemical, in situ hybridization, and semiquantitative reverse transcriptase polymerase chain reaction analyses all indicate that expression of vascular endothelial growth factor is elevated in ulcerative tissue, with vascular endothelial growth factor mRNA being especially pronounced in the hyperplastic epithelium of the wound margin. Flt-1 and KDR protein and mRNA were detected in the papillary vessels in close vicinity to the lesional epithelium of chronic wounds. Although increased expression of vascular endothelial growth factor protein was detected in the epidermis, the intensity of this staining was weak compared with the epidermal staining in psoriatic lesions and compared with the strong vascular endothelial growth factor mRNA signal in chronic wounds and psoriasis. To analyze whether this apparent decrease in immunoreactivity could be the result of degradation of vascular endothelial growth factor by proteolytic activities from the wound environment, we examined the stability of recombinant vascular endothelial growth factor in wound fluid from chronic leg ulcers. As demonstrated by sodium dodecyl sulfate polyacrylamide gel electrophoresis, incubation of rVEGF165 with chronic, but not acute, wound fluid resulted in rapid proteolytic degradation of rVEGF165. Protease inhibitor studies indicate that serine proteases, such as plasmin, are involved in this degradation. Together, our data show that, although vascular endothelial growth factor expression is elevated in chronic wounds, increased proteolytic activity in this environment results in its degradation, which may contribute to an impaired wound healing response.
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PMID:Expression and proteolysis of vascular endothelial growth factor is increased in chronic wounds. 1088 1

To evaluate the relation between hypervascularization and vascular endothelial growth factor (VEGF) in the thyroid glands of patients with Graves disease, 19 Graves disease tissues and 6 normal thyroid tissues were studied by immunohistochemistry, in situ hybridization (ISH), and reverse transcriptase-polymerase chain reaction. The mean microvascular densities per follicle and per millimeter of the thyroid follicles' circumferential length in the Graves disease tissues (mean 3.37 and 13.91) were significantly higher than those in the normal thyroid tissues (mean 2.15 and 7.28) (tied P = .0005, P = .0185, and P < .05, respectively). An antibody against VEGF markedly reacted with hyperplastic follicular cells in Graves disease. The intensity was especially strong in the cells covering papillary growth regions containing accumulated microvessels. By ISH, VEGF messenger RNA (mRNA) signals were also detected in the hyperplastic follicular cells in Graves disease tissues and were especially strong in papillary growth regions. The VEGF receptor-1 (Flt-1) protein and mRNA were observed in endothelial cells of all Graves disease tissues. These findings suggest that hypervascularity in Graves disease tissues is related to upregulated VEGF expression in hyperplastic follicles.
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PMID:Expression of vascular endothelial growth factor (VEGF) and VEGF receptor-1 (Flt-1) in Graves disease possibly correlated with increased vascular density. 1117 89

Vascular endothelial growth factor C (VEGF-C) is the only factor known to cause lymphangiogenesis. We studied the correlation between VEGF-C and vascular endothelial growth factor receptor-3 (VEGFR-3) expression of 85 primary gastric cancers by reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry, and the results were correlated with the number of lymphatic vessels, stained with anti-VEGFR-3 antibody. RT-PCR and immunohistology demonstrated that VEGF-C was mainly produced from cancer cells, but not from stromal elements. Morphologically, VEGFR-3 expression was detected in the endothelial cells of the stromal lymphatic vessels. There was a statistically positive correlation between the incidence of VEGF-C and VEGFR-3 mRNA expression in the primary tumours (P=0.0002). The number of VEGFR-3-positive lymphatic vessels in VEGF-C mRNA positive tumours was significantly larger than that in VEGF-C-negative tumours. The number of VEGFR-3-positive vessels in the tumour stroma was closely related to the grade of lymphatic invasion of gastric cancer. These results strongly indicate that VEGF-C may induce the proliferation of lymphatic vessels in the stroma of primary gastric cancer via activation of VEGFR-3, expressed on the endothelial cells of lymphatic vessels. In these circumstances, cancer cells can easily invade the lymphatic vessel, because of the increase of the contact points of cancer cells with the lymphatic vessels.
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PMID:Lymphangiogenesis and the vascular endothelial growth factor receptor (VEGFR)-3 in gastric cancer. 1131 81

The effects of exogenous vascular endothelial growth factor (VEGF) on angiogenesis, blood-brain barrier permeability and astroglial proliferation in the adult rat CNS in situ were investigated. Recombinant human VEGF(165) (25 or 50 ng/ml) was delivered for up to 1 week using either intracerebral osmotic minipumps or less traumatic subdural gelatin sponge placement. By 3 days, VEGF delivery caused significantly increased cerebral angiogenesis (25 ng/ml was most effective) in both experimental models when compared to saline controls; VEGF infusion resulted in a 100% increase in an index of vascular proliferation, and gelatin sponge delivery produced a 65% increase. The blood-brain barrier hallmark endothelial glucose transporter-1 was not present in nascent vascular sprouts. Infusion of VEGF produced extensive protein leakage that persisted after saline-induced permeability was mostly resolved, while gelatin sponge administration caused milder barrier dysfunction. Administration of the angiogenic factor had unexpected proliferative effects on astroglia in both models, resulting in an 80-85% increase in mitotically active astroglia when compared to controls. Immunohistochemical results and semi-quantitative reverse transcriptase-polymerase chain reaction indicated that the VEGF receptors flk-1 and flt-1 were up-regulated in response to the infusion trauma; flt-1 was localized to reactive astroglia, while flk-1 was expressed in vascular endothelium but predominantly in neuronal somata and processes adjacent to the delivery site. mRNA for the VEGF(121), VEGF(165) and VEGF(188) isoforms was also increased after delivery of the recombinant protein. These data show that VEGF application has substantial proliferative effects on CNS endothelium and astroglia and causes up-regulation of its own message. Flt-1 and flk-1 receptor mRNAs and proteins are up-regulated in both vascular and non-vascular cell types following infusion trauma. From these results we suggest that administered VEGF has heretofore unanticipated pleiotrophic effects in the adult CNS.
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PMID:Angiogenic and astroglial responses to vascular endothelial growth factor administration in adult rat brain. 1193 68

Inflammatory breast cancer (IBC) is a specific type of breast tumor that generally has a poor prognosis, in spite of recent advances in treatment. In the present study, semiquantitative reverse transcriptase polymerase chain reaction examination of resected specimens showed that angiogenic factors, not lymphangiogenic factors, are overexpressed in IBC tumors, compared with non-IBC tumors. Immunohistochemical analysis of the specimens revealed a significantly higher population of tumor-infiltrating (TI) endothelial cells (ECs) or endothelial precursor cells (EPCs) in tumor-associated stroma of IBC specimens than in non-IBC specimens. In a previous study, we examined the phenotype of host cells in response to transplanted IBC cells, using an established human IBC xenograft model (WIBC-9) (Shirakawa et al., Cancer Res 2001;61:445-51). The data obtained in that study are consistent with the findings of the present study. To explore the therapeutic potential of blocking vascular endothelial growth factor (VEGF) and angiopoietin (Ang) pathways in IBC, established vectors encoding soluble Flt-1 (sFlt-1) and soluble Tie2 (sTie2) were injected directly into WIBC-9. Both vectors produced growth inhibition ratios of WIBC-9 that were significantly higher than those of a non-IBC xenograft (MC-5). Also, both vectors suppressed WIBC-9 lung metastases. The efficacy correlated with the number of TI ECs/EPCs, which was determined by fluorescence-activated cell sorting. These ECs/EPCs incorporated acetylated lipoprotein and were integrated within a HUVEC monolayer in vitro culture on day 5.
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PMID:Tumor-infiltrating endothelial cells and endothelial precursor cells in inflammatory breast cancer. 1199 2

The goal of this study was to develop a sensitive, simple, and widely applicable assay to measure copy numbers of specific mRNAs using real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), and identify a profile of gene expression closely associated with angiogenesis. We measured a panel of nine potential angiogenesis markers from a mouse transgenic model of prostate adenocarcinoma (TRAMP) and a mouse skin model of vascular endothelial growth factor (VEGF)-driven angiogenesis. In both models, expression of VEGF correlated with expression of mRNAs encoding other angiogenic cytokines (angiopoietin-1 and angiopoietin-2), endothelial cell receptor tyrosine kinases (Flt-1, KDR, Tie-1), and endothelial cell adhesion molecules (VE-cadherin, PECAM-1). Relative to control, in dermis highly stimulated by VEGF, the Ang-2 mRNA transcript numbers increased 35-fold, PECAM-1 and VE-cadherin increased 10-fold, Tie-1 increased 8-fold, KDR and Flt-1 each increased 4-fold, and Ang-1 increased 2-fold. All transcript numbers were correspondingly reduced in skin with less VEGF expression, indicating a relationship of each of these seven markers with VEGF. Thus, this study identifies a highly efficient method for precise quantification of a panel of seven specific mRNAs that correlate with VEGF expression and VEGF-induced neovascularization, and it provides evidence that real-time quantitative RT-PCR offers a highly sensitive strategy for monitoring angiogenesis.
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PMID:Molecular profiling of angiogenesis markers. 1210 83

Tumors require a blood supply for growth and hematogenous metastases. Until recently, most research in this area has focused on the role of angiogenesis, the recruitment of new vessels into a tumor from preexisting vessels. Previously, in a study of breast cancer (IBC), in which we used established inflammatory breast cancer (IBC) xenografts (WIBC-9) originating from a patient with IBC (Shirakawa et al., Cancer Res 2001:61:445-451), we reported observing vasculogenic mimicry (VM), a condition in which bloodstreams within cancer tissue are not accompanied by a lining of endothelial cells (ECs) (Shirakawa et al., Cancer Res 2002:62:560-566). In the present study, we examined 331 surgically resected breast cancer specimens for evidence of VM, using immunohistochemistry and laser-captured microdissection (LCM) followed by nested reverse transcriptase polymerase chain reaction (RT-PCR). Surprisingly, 7.9% (26 specimens) of the 331 specimens exhibited evidence of VM. Of these 26 VM specimens, 84.6% (22 specimens) exhibited pseudo-comedo formation. RT-PCR analysis of 8 microdissected typical VM specimens revealed expression of Tie-2, Flt-1, thrombin receptor and CD31 in 63, 50, 0 and 0% of specimens, respectively. In contrast, results of RT-PCR analysis of 8 specimens from non-VM tumors were negative for expression of these genes. The 26 VM cases tended to have a higher percentage of hematogenous recurrence (p = 0.059) and a lower percentage of 5-year survival (p = 0.071) than the 305 non-VM cases. However, there were no significant differences in tumor size, lymph node metastasis, estrogen receptors or progesterone receptors between the 2 groups (p > 0.1). Our results suggest that the existence of VM increases the likelihood of hematogenous metastases and is in inverse proportion to prognosis.
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PMID:Vasculogenic mimicry and pseudo-comedo formation in breast cancer. 1211 83

Arteriogenic erectile dysfunction is associated with impairment of vascular perfusion to the erectile components of the penis. Animal studies have identified insulin-like growth factor (IGF-I) and vascular endothelial growth factor (VEGF) as penile angiogenic growth factors, but the role of these factors in humans is not well understood. We evaluated the ex vivo expression of IGF-I, VEGF, and their receptors (IGF-IR, Flt-1, and KDR) in human penile cavernosal smooth muscle cells (HCSMCs) to identify cellular and molecular pathways involved in the regulation of penile tissue vascularity. Primary culture was initiated with explants of human corpora cavernosa, and early passage (3-5) cells were used for these evaluations. Cultures were examined to verify the presence of smooth muscle cells and the absence of endothelial cell contamination. Specific monoclonal antibodies were used to localize growth factors and their receptors. To evaluate gene expression of VEGF, Flt-1, and KDR, total RNA was extracted from cavernosal cells and subjected to reverse transcriptase-polymerase chain reaction (RT-PCR) using custom synthesized primers. To study the effect on cell proliferation, 10000 cells/well were exposed to varying concentrations of VEGF (0-50 ng/mL). At specified time periods the cells were trypsinized and counted. IGF-I and VEGF and their receptors were localized in the cultures, which were positive for the presence of smooth muscle cells and negative for endothelial cell contamination. RT-PCR evaluation revealed the expression of four splice variants of VEGF messenger RNA (VEGFs 121, 145, 165, and 189) and two of its receptors (Flt-1 and KDR). VEGF165 and VEGF121 were the most abundant forms of messenger RNA and Flt-1 appeared to be the most prominent receptor type in these cells. Exposure to VEGF elicited a twofold to threefold increase in the proliferation of HCSMCs. HCSMCs express both IGF-I and VEGF and their receptors, which may be important in the control of vascularity in human penile architecture.
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PMID:Ex vivo expression of angiogenic growth factors and their receptors in human penile cavernosal cells. 1251 88

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.
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PMID:Cardiac myofibroblasts: a novel source of vascular endothelial growth factor (VEGF) and its receptors Flt-1 and KDR. 1267 42


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