Transforming Growth Factor-β Induces Expression of Vascular Endothelial Growth Factor in Human Retinal Pigment Epithelial Cells: Involvement of Mitogen-Activated Protein Kinases

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-β1. TGF-β1, β2, and β3 were the potent inducers of VEGF secretion by HRPE cells whereas bFGF, PDGF, TGF-α, and GM-CSF had no effects. TGF-β receptor type II antibody significantly reversed induction of VEGF secretion by TGF-β. In contrast activin, inhibin and BMP, members of TGF-β super family, had no effects on VEGF expression in HRPE. VEGF mRNA levels and protein secretion induced by TGF-β were significantly inhibited by SB203580 and U0126, inhibitors of MAP kinases, but not by staurosporine and PDTC, protein kinase C and NF-κB pathway inhibitors, respectively. TGF-β also induced VEGF expression by fibroblasts derived from human choroid of eye. TGF-β 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.