Abstract
Vascular endothelial growth factor (VEGF) is a major agent in choroidal and retinal neovascularization, events associated with age-related macular degeneration (AMD) and diabetic retinopathy. Retinal pigment epithelium (RPE), strategically located between retina and choroid, plays a critical role in retinal disorders. We have examined the effects of various growth factors on the expression and secretion of VEGF by human retinal pigment epithelial cell cultures (HRPE). RT-PCR analyses revealed the presence of three isoforms of mRNA corresponding to VEGF 121, 165, and 189 that were up regulated by TGF-beta1. TGF-beta1, beta2, and beta3 were the potent inducers of VEGF secretion by HRPE cells whereas bFGF, PDGF, TGF-alpha, and GM-CSF had no effects. TGF-beta receptor type II antibody significantly reversed induction of VEGF secretion by TGF-beta. In contrast activin, inhibin and BMP, members of TGF-beta super family, had no effects on VEGF expression in HRPE. VEGF mRNA levels and protein secretion induced by TGF-beta were significantly inhibited by SB203580 and U0126, inhibitors of MAP kinases, but not by staurosporine and PDTC, protein kinase C and NF-kappaB pathway inhibitors, respectively. TGF-beta also induced VEGF expression by fibroblasts derived from human choroid of eye. TGF-beta induction of VEGF secretion by RPE and choroid cells may play a significant role in choroidal neovascularization (CNV) in AMD. Since the secretion of VEGF by HRPE is regulated by MAP kinase pathways, MAP kinase inhibitors may have potential use as therapeutic agents for CNV in AMD.
MeSH terms
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Antibodies / pharmacology
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Cells, Cultured
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Choroid / drug effects
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Choroid / enzymology
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Dactinomycin / pharmacology
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / pharmacology
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Enzyme Inhibitors / therapeutic use
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Fibroblasts / drug effects
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Fibroblasts / enzymology
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Humans
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MAP Kinase Signaling System / drug effects
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MAP Kinase Signaling System / physiology*
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Matrix Metalloproteinases / drug effects
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Matrix Metalloproteinases / metabolism
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Neovascularization, Pathologic / drug therapy
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Neovascularization, Pathologic / enzymology
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Neovascularization, Pathologic / genetics
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Pigment Epithelium of Eye / drug effects
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Pigment Epithelium of Eye / enzymology
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Pigment Epithelium of Eye / metabolism*
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Protein Isoforms / genetics
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Protein Serine-Threonine Kinases
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RNA, Messenger / drug effects
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RNA, Messenger / metabolism
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Receptor, Transforming Growth Factor-beta Type II
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Receptors, Transforming Growth Factor beta / drug effects
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Receptors, Transforming Growth Factor beta / metabolism
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Retinal Diseases / drug therapy
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Retinal Diseases / enzymology
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Retinal Diseases / genetics
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Transforming Growth Factor beta / antagonists & inhibitors
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Transforming Growth Factor beta / metabolism*
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Vascular Endothelial Growth Factor A / genetics*
Substances
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Antibodies
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Enzyme Inhibitors
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Protein Isoforms
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RNA, Messenger
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Receptors, Transforming Growth Factor beta
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Transforming Growth Factor beta
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Vascular Endothelial Growth Factor A
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Dactinomycin
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type II
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Matrix Metalloproteinases