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      Upregulation of Retinal Vascular Endothelial Growth Factor mRNAs in Spontaneously Diabetic Rats without Ophthalmoscopic Retinopathy


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          Vascular endothelial growth factor (VEGF) has recently been shown to be involved in the pathogenesis of proliferative diabetic retinopathy. However, its involvement in the development of the early phase of diabetic retinopathy is not fully understood. In this study we investigated the retinal VEGF mRNA level in spontaneously diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats, a model of non-insulin-dependent diabetes, without overt retinopathy, using quantitative reverse-transcription polymerase chain reaction. The retinal VEGF mRNA level was 2.2 times higher (p < 0.0005) in OLETF rats than in control rats at the age of 60 weeks. Moreover, their retinal mRNA level was positively correlated with serum concentration of advanced glycation end products (AGEs) but not to serum glucose concentration. Furthermore, the peak latency of the oscillatory potentials in the electroretinogram, one of the most sensitive markers for the early phase of diabetic retinopathy, was significantly prolonged in OLETF rats (p < 0.05), being also correlated with the serum AGE concentration. The results thus suggest that AGEs, which are formed acceleratedly in diabetic conditions, are involved in the development of the early phase of diabetic retinopathy probably through the induction of retinal VEGF mRNAs.

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          Most cited references5

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          Possible participation of autocrine and paracrine vascular endothelial growth factors in hypoxia-induced proliferation of endothelial cells and pericytes.

          Hypoxia is the principal factor that causes angiogenesis. These experiments were conducted to explore how it induces the proliferation of vascular cells, a key step in angiogenesis. Human umbilical vein endothelial cells and bovine retinal pericytes were grown in controlled atmosphere culture chambers containing various concentrations of oxygen. The numbers of both endothelial cells and pericytes increased significantly under hypoxic conditions; the O2 concentrations that achieved maximal growth promotion were 10% for endothelial cells and 2.5% for pericytes. Quantitative reverse transcription-polymerase chain reaction analysis revealed that mRNAs coding for the secretory forms of vascular endothelial growth factor (VEGF), a mitogen specific to endothelial cells, were present in both endothelial cells and pericytes and that their levels increased significantly in the two cell types as the atmospheric O2 concentration decreased. The two genes for VEGF receptors, kinase insert domain-containing receptor (kdr) and fms-like tyrosine kinase 1 (flt1), were found to be constitutively expressed in endothelial cells, and their relative mRNA levels were ranked in that order. On the other hand, only flt1 mRNA was detected in pericytes under hypoxic conditions. Furthermore, most antisense oligodeoxyribonucleotides complementary to VEGF mRNAs efficiently inhibited DNA synthesis in endothelial cells cultured under hypoxic conditions. These results indicate that autocrine and paracrine VEGFs may take part in the hypoxia-induced proliferation of endothelial cells.
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            Advanced Glycation End Products-driven Angiogenesisin Vitro

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              Receptor-mediated toxicity to pericytes of advanced glycosylation end products: a possible mechanism of pericyte loss in diabetic microangiopathy.

              The influence of advanced glycosylation end products (AGE) on bovine retinal pericytes was investigated. When pericytes were cultured with AGE-bovine serum albumin (BSA), pericyte growth was significantly retarded in a dose-dependent manner. They also exhibited an immediate toxicity to pericytes. However, MRC-5 human fibroblasts were totally resistant to AGE-BSA. Moreover, antisense oligonucleotides complementary to mRNA coding for AGE receptor were found to reverse the AGE-induced decrease in viable pericyte number, although the mRNA level was about one order of magnitude lower in pericytes than in the fibroblasts. These results indicate that pericytes may possess a peculiar sensitivity to AGE, and that AGE ligand-receptor interactions may play an important role in the pathogenesis of pericyte loss, the principal change in diabetic microangiopathies.

                Author and article information

                Ophthalmic Res
                Ophthalmic Research
                S. Karger AG
                December 1998
                05 October 1998
                : 30
                : 6
                : 333-339
                Departments of a Ophthalmology and b Biochemistry, Kanazawa University School of Medicine, Kanazawa, c Discovery Research Laboratory III and d Planning, Discovery Research, R & D, Kissei Pharmaceutical Co., Matsumoto, and e Department of Laboratory Medicine, School of Medicine, University of Tokushima, Japan
                55493 Ophthalmic Res 1998;30:333–339
                © 1998 S. Karger AG, Basel

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                Page count
                Figures: 4, Tables: 2, References: 24, Pages: 7
                Original Paper

                Vision sciences,Ophthalmology & Optometry,Pathology
                Advanced glycation end products,Vascular endothelial growth factor,Reverse-transcription polymerase chain reaction,Spontaneously diabetic rats,Electroretinogram,Oscillatory potentials


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