Vasculotropin-VEGF Stimulates Retinal Capillary Endothelial Cells through an Autocrine Pathway

Simorre-Pinatel, V; Guerrin, Marina; Chollet, Pascale; Pénary, Marie; Clemens, Stephan; Malecaze, F; Plouët, Jean

doi:10.1097/00006982-199515020-00022

Cited by 38 publications

(47 citation statements)

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“…Among them, Mü ller cells and RPE are believed to be the major source of VEGF in the retina, and endothelial cells to be the primary target of VEGF , Dorey et al 1996. Cultured vascular endothelial cells also express high levels of VEGF in an autocrine manner (Simorre--Pinatel et al 1994). In the present study, we have investigated the effect of PEDF on the regulation of VEGF expression in cultured retinal Müller cells and RCEC.…”

Section: Discussionmentioning

confidence: 94%

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Pigment epithelium-derived factor downregulates vascular endothelial growth factor (VEGF) expression and inhibits VEGF–VEGF receptor 2 binding in diabetic retinopathy

Zhang¹,

Wang²,

Gao³

et al. 2006

Journal of Molecular Endocrinology

226

152

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It has been shown that the balance between vascular endothelial growth factor (VEGF), a major angiogenic stimulator, and pigment epithelium-derived factor (PEDF), a potent angiogenic inhibitor, is critical for the regulation of vascular permeability and angiogenesis. However, the regulation of the balance is largely unclear. The present study demonstrated that there is a reciprocal interaction between VEGF and PEDF in the retina. PEDF significantly decreased VEGF expression in both retinal capillary endothelial cells (RCEC) and Mü ller cells. This PEDF effect was confirmed in the retina of rats with oxygen-induced retinopathy. Silencing of the PEDF gene by siRNA in Mü ller cells resulted in a significant upregulation of VEGF expression at both the RNA and protein levels, suggesting that PEDF is an endogenous negative regulator of VEGF. The further study of the mechanism showed that PEDF inhibited hypoxia-induced increases in VEGF promoter activity, HIF-1 nuclear translocation and mitogen activated protein kinase phosphorylation. These results suggest that PEDF inhibits VEGF expression at the transcriptional level. In addition, PEDF effectively inhibited VEGF binding to RCEC. Moreover, in vitro receptor-binding assay demonstrated that PEDF competed with VEGF for binding to VEGF receptor 2, which may represent a new mechanism for PEDF activity. On the other hand, VEGF significantly downregulated PEDF expression in RCEC, but not in retinal Mü ller cells, suggesting a VEGF receptormediated process. These results suggest that the reciprocal regulation between VEGF and PEDF may play a role in angiogenic control. The decrease in PEDF levels in the retina is at least partially responsible for the increase in VEGF expression and subsequent vascular leakage and neovascularization in diabetes.

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Section: Discussionmentioning

confidence: 94%

“…RCEC is the major component of the BRB and serves as the primary target of VEGF (Hatcher et al 1998). Cultured primary RCEC have been shown to produce high levels of VEGF (Simorre-Pinatel et al 1994). The retinal Mü ller cell has been recognized as a major source of VEGF in the retina (Hata et al 1995).…”

Section: Resultsmentioning

confidence: 99%

Pigment epithelium-derived factor downregulates vascular endothelial growth factor (VEGF) expression and inhibits VEGF–VEGF receptor 2 binding in diabetic retinopathy

Zhang¹,

Wang²,

Gao³

et al. 2006

Journal of Molecular Endocrinology

226

152

View full text Add to dashboard Cite

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“…The heterogeneity of the molecular species generated from V189 is in good agreement with the biological actions expected from an angiogenic/survival factor such as VEGF: nonmitogenic when stored in the extracellular matrix; a strong mitogen with a weak ability to circulate when matured by urokinase; and finally a weak diffusible mitogen. Since intact V189 cannot be matured by the vascular endothelial target cells when added exogenously, it would be of interest to study the influence of V189 overexpression on target cell growth rate, since it has been demonstrated that under certain conditions these cells may produce one or all different molecular forms of VEGF (38), suggesting the possibility of an autocrine loop.…”

Section: Discussionmentioning

confidence: 99%

Extracellular Cleavage of the Vascular Endothelial Growth Factor 189-Amino Acid Form by Urokinase Is Required for Its Mitogenic Effect

Plouët

Moro

Bertagnolli

et al. 1997

Journal of Biological Chemistry

211

190

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Alternative splicing of vascular endothelial growth factor (VEGF) mRNA results in three distinct molecular forms of 121 or 165 (V165) amino acids that are released in the conditioned medium of cultured cells and one longer isoform of 189 amino acids (V189) that remains cell-associated. V189 has been expressed in wild type CHO-K1 cells and in glycosaminoglycan-deficient pgsA-745 Chinese hamster ovary (CHO) mutant cells. It could be released from CHO-K1 cell membranes by heparin or a synthetic peptide designed on the sequence encoded by exon 6 but was freely released from CHO mutant cells. In both cases, the immunoreactive V189 was mainly released as a 40-kDa cleaved form, provided that the serine protease urokinase, but not plasmin, was active. Recombinant V189 was purified from insect cells infected with a recombinant baculovirus as a nonmitogenic 50-kDa precursor that binds to the receptor Flt-1 but not to Flk-1. It could be matured by urokinase as a 38-kDa fragment able to bind to Flk-1 and to trigger cell proliferation. V165 and V189, however, could be cleaved by plasmin as 34-kDa fragments that exhibit a decreased mitogenic activity. These findings indicate that the carboxyl-terminal domain of V189 masks its binding domain to Flk-1.

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“…Again, the consequence of this would be thrombogenesis. Diminished circulation or microthrombus formation may occur in such lesions, giving rise to hypoxia, the major factor triggering VEGF expression in both endothelial cells and pericytes (20,(37)(38)(39)(40). In such circumstances, angiogenesis would further proceed, which may eventually lead to the clinical expression of diabetic microangiopathies, exemplified by proliferative retinopathy.…”

Section: Discussionmentioning

confidence: 99%

Advanced Glycation End Products-driven Angiogenesis in Vitro

Yamagishi

Yonekura

Yamamoto

et al. 1997

Journal of Biological Chemistry

260

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This study was undertaken to determine whether and how advanced glycation end products (AGE), senescent macroproteins accumulated in various tissues under hyperglycemic states, cause angiogenesis, the principal vascular derangement in diabetic microangiopathy. We first prepared AGE-bovine serum albumin (BSA) and anti-AGE antiserum using AGE-RNase A. Then AGE-BSA was administered to human skin microvascular endothelial cells in culture, and their growth was examined. The AGE-BSA, but not nonglycated BSA, was found to induce a statistically significant increase in the number of viable endothelial cells as well as their synthesis of DNA. The increase in DNA synthesis by AGE-BSA was abolished by anti-AGE antibodies. AGE-BSA also stimulated the tube formation of endothelial cells on Matrigel. We obtained the following evidence that it is vascular endothelial growth factor (VEGF) that mainly mediates the angiogenic activities of AGE. Glucose and other reducing sugars can react nonenzymatically with the amino groups of proteins to form reversible Schiff bases and, then, Amadori products. These early glycation products undergo further complex reactions such as rearrangement, dehydration, and condensation to become irreversibly crosslinked, heterogeneous fluorescent derivatives termed advanced glycation end products (AGE) 1 (1). The formation and accumulation of AGE in various tissues have been known to progress during normal aging and at an extremely accelerated rate in diabetes mellitus. This has been implicated in the development of diabetic micro-and macro-vascular complications (1), which may account for the disabilities and high mortality rate in patients with this disease (2).Microvessels are composed of only two types of cells, endothelial cells and pericytes, and have been known to show both functional and structural abnormalities during prolonged diabetic exposure, resulting in the deleterious effects on the organs that they supply (3-5). Using pericyte-endothelial cell co-culture systems, we have shown previously that pericytes can not only regulate the growth but also preserve the prostacyclin-producing ability and protect against lipid peroxide-induced injury of endothelial cells (6). This has provided a basis for understanding how diabetic retinopathy develops consequent to "pericyte loss," the earliest histopathological hallmark in diabetic retinopathy (5, 7).Recently, we have found that AGE exert a growth inhibitory effect and a cell type-specific immediate toxicity on pericytes through interactions with their receptor for AGE (RAGE), a cell surface receptor belonging to the immunoglobulin superfamily (8), and have proposed a novel mechanism for pericyte loss (9). The AGE-induced, RAGE-mediated decrease in pericyte number would then indirectly cause angiogenesis (6,9).In the present study, we investigated the effects of AGE on the growth and tube formation of human skin microvascular endothelial cells, the key steps of angiogenesis. We demonstrate that AGE exert angiogenic activities directly on microvasc...

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Vasculotropin-VEGF Stimulates Retinal Capillary Endothelial Cells through an Autocrine Pathway

Cited by 38 publications

References 0 publications

Pigment epithelium-derived factor downregulates vascular endothelial growth factor (VEGF) expression and inhibits VEGF–VEGF receptor 2 binding in diabetic retinopathy

Pigment epithelium-derived factor downregulates vascular endothelial growth factor (VEGF) expression and inhibits VEGF–VEGF receptor 2 binding in diabetic retinopathy

Extracellular Cleavage of the Vascular Endothelial Growth Factor 189-Amino Acid Form by Urokinase Is Required for Its Mitogenic Effect

Advanced Glycation End Products-driven Angiogenesis in Vitro

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