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

Retinal pigment epithelial (RPE) cells secrete vascular endothelial growth factor (VEGF), a cytokine known to promote angiogenesis. Results from RNase protection assays (RPAs) show that RPE from non‐diabetic human donors and from adult retinal pigment epithelium‐19 (ARPE‐19) cells expressed significant bone morphogenetic protein‐4 (BMP‐4) message. In addition, ARPE‐19 cells cultured in high glucose (25 mM), compared to those in physiological glucose (5.5 mM) released significantly more BMP‐4 into the conditioned media (CM). However, the effect of BMP‐4 on the release of VEGF by ARPE‐19 cells has not been studied. Accordingly, ARPE‐19 cells were treated with BMP‐4 to determine VEGF secretion. BMP‐4 and VEGF levels in the CM and cell lysates were measured by enzyme‐linked immunosorbent assay (ELISA). Cells treated with exogenous BMP‐4 had higher VEGF in the CM and this treatment effect was dose‐ and time‐dependent, while cell lysates had low levels of VEGF. Addition of cycloheximide (CHX) or actinomycin‐D (ACT) significantly reduced VEGF secretion from cells treated with BMP‐4, suggesting that the BMP‐4‐induced secretion of VEGF requires new RNA and protein synthesis. Our results suggest that BMP‐4 may play a role in the regulation of ocular angiogenesis associated with diabetic retinopathy (DR) by stimulating VEGF release from RPE cells. J. Cell. Biochem. 98: 1196–1202, 2006. © 2006 Wiley‐Liss, Inc.