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      A Common 936 C/T Mutation in the Gene for Vascular Endothelial Growth Factor Is Associated with Vascular Endothelial Growth Factor Plasma Levels

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          Background: Vascular endothelial growth factor (VEGF) is an important regulator of angiogenesis. Strong interindividual variations of VEGF plasma levels have been reported previously. Aim of the present study was to search for mutations in the 3′ untranslated region (3′-UTR) of the VEGF gene and to analyze their relation to VEGF plasma levels. Methods: The complete 3′-UTR (nucleotide 700–2622) of the VEGF gene was screened for sequence variations by single-strand conformation polymorphism (SSCP) analysis. Frequencies of mutated alleles were determined in 119 healthy subjects; VEGF plasma levels were analyzed in a subgroup of 23 healthy men aged 18–36 years. Results: Three novel mutations (702 C/T, 936 C/T, 1612 G/A) were found, allele frequencies of 702T, 936T and 1612A were of 0.017, 0.160 and 0.471, respectively. VEGF plasma levels were significantly lower in carriers of the 936T allele (9.1 ± 2.7 pg/ml, mean ± SEM) than in noncarriers (28.0 ± 5.5 pg/ml, p = 0.033), whereas the 702 C/T and the 1612 G/A mutations showed no association with VEGF plasma levels. The 936 C/T exchange led to the loss of a potential binding site for transcription factor AP-4, although the functionality of this binding site remains unclear. Conclusion: We have found three common mutations in the VEGF gene; one of them, a 936 C/T exchange, may be an important determinant of VEGF plasma levels.

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          Most cited references 7

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          Vascular permeability factor: a tumor-derived polypeptide that induces endothelial cell and monocyte procoagulant activity, and promotes monocyte migration

           J Brett,  F Wang,  M Clauss (1990)
          Systemic infusion of low concentrations of tumor necrosis factor/cachectin (TNF) into mice that bear TNF-sensitive tumors leads to activation of coagulation, fibrin formation, and occlusive thrombosis exclusively within the tumor vascular bed. To identify mechanisms underlying the localization of this vascular procoagulant response, a tumor-derived polypeptide has been purified to homogeneity from supernatants of murine methylcholanthrene A-induced fibrosarcomas that induces endothelial tissue factor synthesis and expression (half- maximal response at approximately 300 pM), and augments the procoagulant response to TNF in a synergistic fashion. This tumor- derived polypeptide was identified as the murine homologue of vascular permeability factor (VPF) based on similar mobility on SDS-PAGE, an homologous NH2-terminal amino acid sequence, and recognition by a monospecific antibody to guinea pig VPF. In addition, VPF was shown to induce monocyte activation, as evidenced by expression of tissue factor. Finally, VPF was shown to induce monocyte chemotaxis across collagen membranes and endothelial cell monolayers. Taken together, these results indicate that VPF can modulate the coagulant properties of endothelium and monocytes, and can promote monocyte migration into the tumor bed. This suggests one mechanism through which tumor-derived mediators can alter properties of the vessel wall.
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            Post-transcriptional regulation of vascular endothelial growth factor by hypoxia.

            The major control point for the hypoxic induction of the vascular endothelial growth factor (VEGF) gene is the regulation of the steady-state level of the mRNA. We previously demonstrated a discrepancy between the transcription rate and the steady-state mRNA level induced by hypoxia. This led us to examine the post-transcriptional regulation of VEGF expression. Actinomycin D experiments revealed that hypoxia increased VEGF mRNA half-life from 43 +/- 6 min to 106 +/- 9 min. Using an in vitro mRNA degradation assay, the half-life of VEGF mRNA 3'-untranslated region (UTR) transcripts were also found to be increased when incubated with hypoxic versus normoxic extracts. Both cis-regulatory elements involved in VEGF mRNA degradation under normoxic conditions and in increased stabilization under hypoxic conditions were mapped using this degradation assay. A hypoxia-induced protein(s) was found that bound to the sequences in the VEGF 3'-UTR which mediated increased stability in the degradation assay. Furthermore, genistein, a tyrosine kinase inhibitor, blocked the hypoxia-induced stabilization of VEGF 3'-UTR transcripts and inhibited hypoxia-induced protein binding to the VEGF 3'-UTR. These findings demonstrate a significant post-transcriptional component to the regulation of VEGF.
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              Oldest fossil record of gliding in rodents


                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                December 2000
                10 January 2001
                : 37
                : 6
                : 443-448
                Karl-Franzens University Graz, Department for Internal Medicine, Division of Angiology, Graz, Austria
                54076 J Vasc Res 2000;37:443–448
                © 2000 S. Karger AG, Basel

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                Page count
                Figures: 3, Tables: 2, References: 31, Pages: 6
                Research Paper


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