Transforming growth factor‐β induces expression of vascular endothelial growth factor in human retinal pigment epithelial cells: Involvement of mitogen‐activated protein kinases

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.

Bone morphogenetic protein‐4 enhances vascular endothelial growth factor secretion by human retinal pigment epithelial cells

“…Our experimental results seem different from a recent study, using HRPE cells, in which BMP-4 did not affect VEGF secretion [Nagineni et al, 2003]. It is possible that the ARPE-19 cells used in our study have different gene expression than the HRPE cells in that study.…”

“…It is possible that the ARPE-19 cells used in our study have different gene expression than the HRPE cells in that study. In addition, 10 ng/ml of BMP-4 was used in our study, as compared with a higher concentration of 40 ng/ ml used in the reported study [Nagineni et al, 2003]. Furthermore, in our study, BMP-4 treatment of ARPE-19 cells shows significant time-and dosedependency of VEGF secretion (Figs.…”

“…5). At present, the transduction pathways of BMP-4-induced VEGF production remain to be established [Nagineni et al, 2003;He and Chen, 2005].…”

“…Pfeffer et al [1994] showed that human RPE cells produce transforming growth factor-beta 2 (TGF-β2) and Pascal et al [1999] showed that TGF-β2 production can be affected by different glucose concentrations. Three specific isoforms of the transforming growth factorbeta (TGF-β) were found to increase VEGF in primary cultured human retinal pigment epithelium (HRPE) cells [Nagineni et al, 2003] and VEGF is crucial for angiogenesis [Saadeh et al, 1999]. VEGF has also been identified as an initiator of proliferative diabetic retinopathy (DR) and found to be related to neovascularization [Aiello and Wong, 2000].…”

Spatiotemporal protein distribution of TGF‐βs, their receptors, and extracellular matrix molecules during embryonic tendon development

“…Several studies have reported the ability of VEGF to induce TGF-␤1 mRNA expression both in healing tendon and in tendon fibroblasts in vitro (Zhang et al, 2003;Wang et al, 2005). Alternatively, TGF-␤s have also been demonstrated to induce VEGF secretion in cultures of human retinal pigment epithelial cells (Nagineni et al, 2003). TGF-␤s are known to induce expression of fibronectin, which is involved in angiogenesis (Balza et al, 1988;Nicosia et al, 1993).…”