Human retinal epithelium produces and responds to placenta growth factor.
BACKGROUND
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.


METHODS
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.


RESULTS
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-beta1, and beta2) 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.


CONCLUSIONS
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.
Hollborn
Margrit
M
Department of Ophthalmology, Eye Clinic, University of Leipzig Medical Faculty, Liebigstrasse 10-14, 04103 Leipzig, Germany. hollbm@medizin.uni-leipzig.de
Tenckhoff
Solveig
S
Seifert
Marlen
M
Köhler
Stephanie
S
Wiedemann
Peter
P
Bringmann
Andreas
A
Kohen
Leon
L
D015153:Blotting, Western; D002478:Cells, Cultured; D002633:Chemotaxis; D016207:Cytokines / Q000494:pharmacology; D004247:DNA / Q000096:biosynthesis; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D039942:Neuropilin-1 / Q000235:genetics; D039943:Neuropilin-2 / Q000235:genetics; D010766:Phosphorylation; D010857:Pigment Epithelium of Eye / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000235:genetics* / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics
D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D039943:Neuropilin-2; C000608036:PGF protein, human; D011257:Pregnancy Proteins; D012333:RNA, Messenger; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000072483:Placenta Growth Factor; D039942:Neuropilin-1; D004247:DNA; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3