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Originally published In Press as doi:10.1167/iovs.08-3194 on April 15, 2009
 (Investigative Ophthalmology and Visual Science. 2009;50:4452-4459.)
© 2009 by The Association for Research in Vision and Ophthalmology, Inc.
doi:10.1167/iovs.08-3194
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Effects of Thrombin on RPE Cells Are Mediated by Transactivation of Growth Factor Receptors

Margrit Hollborn,1 Carola Petto,1 Anja Steffen,1,2 Susanne Trettner,1,2 Andrea Bendig,1,2 Peter Wiedemann,1 Andreas Bringmann,1 and Leon Kohen1,3

1From the Department of Ophthalmology and Eye Hospital, and the 2Interdisciplinary Center of Clinical Research (IZKF), University of Leipzig, Leipzig, Germany; and the 3Helios Klinikum Aue, Aue, Germany.

PURPOSE. To determine the expression of blood coagulation factors and thrombin receptors in retinal pigment epithelial (RPE) cells and whether the effects of thrombin on the chemotaxis and the secretion of VEGF are mediated by transactivation of growth factor receptors.

METHODS. Gene expression in acutely isolated and cultured human RPE cells was evaluated by RT-PCR. Alterations in gene expression and secretion of VEGF were determined by real-time RT-PCR and ELISA, respectively. Chemotaxis was examined with a Boyden chamber assay.

RESULTS. RPE cells expressed the mRNA of the protease-activated receptors PAR1 and -3 and of various coagulation factors (III, V, VII, VIII, and X). Thrombin stimulated the expression and secretion of VEGF-A from RPE cells, decreased the expression of VEGFD, and increased the gene expression of VEGFR-1 (FLT1). The effects on the secretion of VEGF-A and the increase in FLT1 expression were mediated by stimulation of the secretion of TGF-β1 and activation of the TGF-β activin receptor-like kinase. Thrombin stimulated the chemotaxis of RPE cells, and this effect was mediated by transactivation of the PDGF receptor tyrosine kinase.

CONCLUSIONS. The expression of different coagulation factors suggests that RPE cells provide a procoagulant surface for the formation of thrombin from prothrombin via the extrinsic coagulation pathway. Thrombin stimulates the secretion of VEGF-A, the expression of FLT1, and the chemotaxis of RPE cells via transactivation of TGF-β and PDGF receptors, respectively.






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