A selective cyclic integrin antagonist blocks the integrin receptors αvβ3 and αvβ5 and inhibits retinal pigment epithelium cell attachment, migration and invasion
1 Doheny Eye Institute, Departments of Ophthalmology, Keck School of Medicine, University of Southern California 1355 San Pablo Street, Los Angeles 90033, CA, USA
2 Department of Pathology, Keck School of Medicine, University of Southern California, 2011 Zonal Ave HMR 209, Los Angeles, CA 90033, USA
3 Department of Ophthalmology, University of Leipzig, Liebigstrasse 10–14, 04103 Leipzig, Germany
4 Berufsgenossenschaftliche Kliniken Bergmannsheil, University of Bochum, Department of Internal Medicine I, Bürkle-de-la-Camp-Platz 1, D-44789 Bochum, Germany
BMC Ophthalmology 2005, 5:16 doi:10.1186/1471-2415-5-16Published: 29 June 2005
Proliferative vitreoretinopathy (PVR) is a leading cause of blindness after failed retinal reattachment surgery. PVR is characterized by the proliferation, migration and contraction of retinal pigmented epithelial cells (RPE), and these cellular responses are influenced by the expression and function of integrin receptors. The effect of a cyclic integrin antagonist containing the amino acid sequence Arg-Gly-Asp-D-Phe-Val (RGDfV), specific for the integrin receptors αvβ3 and αvβ5, was investigated on basic fibroblast growth factor (bFGF), platelet derived growth factor-BB (PDGF-BB), and serum induced human RPE proliferation, migration, invasion and attachment to the extracellular matrix. Furthermore, the effects of bFGF and PDGF-BB regulated expression of integrins αvβ3 and αvβ5 on RPE cells was examined.
The effect of a cyclic integrin antagonist and a control peptide (0.01 μg/ml to 300 μg/ml) was investigated on serum or cytokine (bFGF or PDGF-BB pretreatment) induced human fetal RPE cell proliferation by H3-thymidine uptake. The effect of the cyclic integrin antagonist on RPE cell attachment onto different extracellular matrices (laminin, collagen IV, fibronectin), RPE cell invasion stimulated by PDGF-BB or serum, and migration stimulated by PDGF-BB, vascular endothelial growth factor (VEGF) or serum was explored. PDGF-BB and bFGF modulation of the integrin receptors αvβ3 and αvβ5 was evaluated by flow cytometry.
The integrin antagonist did not inhibit DNA synthesis stimulated by serum, bFGF, or PDGF-BB treatment. RPE attachment onto fibronectin was inhibited in a concentration range of 1–10 μg/ml (p < 0.05). Attachment of the RPE cells onto collagen IV and laminin was inhibited in a range of 3–10 μg/ml (p < 0.05). Serum and PDGF-BB stimulated migration was inhibited by the cyclic integrin antagonist in a concentration range of 1–10 μg/ml (p < 0.05). Furthermore, the cyclic integrin antagonist inhibited PDGF-BB stimulated RPE cell invasion through fibronectin (3μg/ml: 66% inhibition, p < 0.001). In each of these experiments, the control peptides had no significant effects. PDGF-BB and bFGF pretreatment of RPE cells increased the expression of integrin receptors αvβ3 (bFGF: 1.9 fold, PDGF-BB: 2.3 fold) and αvβ5 (bFGF: 2.9 fold, PDGF-BB: 1.5 fold).
A selective inhibition of the integrin receptors αvβ3 and αvβ5 through a cyclic integrin antagonist is able to inhibit RPE cell attachment, migration and invasion. Since these steps are of importance for the progression of PVR, a cyclic integrin antagonist should be further evaluated for the treatment of this disease.