Human retinal epithelium produces and responds to placenta growth factor

Placenta growth factor (PlGF) is an important co-factor in retinal neovascularization. To examine whether retinal pigment epithelial (RPE) cells may represent a source for PlGF during retinopathy, we determined whether human RPE cells in vitro produce and respond to PlGF. In addition, we determined whether the cells express receptors for PlGF, i.e. flt-1 and neuropilins. Cultured human RPE cells of passages 3-5 were used. The regulation of the PlGF gene and protein expression by growth factors and cytokines was evaluated by quantitative PCR and ELISA. Proliferation rates and chemotaxis were determined by a bromodeoxyuridine and a Boyden chamber assay. Human RPE cells express mRNAs for various members of the vascular endothelial growth factor family and for their receptors, including mRNAs for PlGF, flt-1, KDR, and neuropilins-1 and -2. The expression levels of the mRNAs for neuropilins-1 and -2 were significantly higher than those for flt-1 and KDR. Members of the transforming growth factor (TGF)-beta superfamily of growth factors (BMP-4, TGF-beta 1, and beta 2) were strong inducers of PlGF gene expression, and evoked secretion of PlGF-2 protein by RPE cells. Exogenous PlGF-2 induced chemotaxis in RPE cells and reduced slightly the cell proliferation at high concentrations. The findings that RPE cells produce and respond to PlGF indicate that the factor exerts an autocrine/paracrine action on these cells. It is suggested that increased expression of TGF-beta-related growth factors during diabetic retinopathy may cause PlGF secretion by RPE cells contributing to the stimulation of cell migration as a critical component of the progression of fibrovascular membranes.