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. 2005 Jun 29:5:16.
doi: 10.1186/1471-2415-5-16.

A selective cyclic integrin antagonist blocks the integrin receptors alphavbeta3 and alphavbeta5 and inhibits retinal pigment epithelium cell attachment, migration and invasion

Stephan Hoffmann  1 , Shikun He, Manlin Jin, Marianne Ehren, Peter Wiedemann, Stephen J Ryan, David R Hinton
Affiliations

A selective cyclic integrin antagonist blocks the integrin receptors alphavbeta3 and alphavbeta5 and inhibits retinal pigment epithelium cell attachment, migration and invasion

Stephan Hoffmann et al. BMC Ophthalmol. .

Abstract

Background: 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 alphavbeta3 and alphavbeta5, 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 alphavbeta3 and alphavbeta5 on RPE cells was examined.

Methods: The effect of a cyclic integrin antagonist and a control peptide (0.01 microg/ml to 300 microg/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 alphavbeta3 and alphavbeta5 was evaluated by flow cytometry.

Results: 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 microg/ml (p < 0.05). Attachment of the RPE cells onto collagen IV and laminin was inhibited in a range of 3-10 microg/ml (p < 0.05). Serum and PDGF-BB stimulated migration was inhibited by the cyclic integrin antagonist in a concentration range of 1-10 microg/ml (p < 0.05). Furthermore, the cyclic integrin antagonist inhibited PDGF-BB stimulated RPE cell invasion through fibronectin (3 microg/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 alphavbeta3 (bFGF: 1.9 fold, PDGF-BB: 2.3 fold) and alphavbeta5 (bFGF: 2.9 fold, PDGF-BB: 1.5 fold).

Conclusion: A selective inhibition of the integrin receptors alphavbeta3 and alphavbeta5 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.

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Figures

Figure 1
Figure 1
A. Expression of the integrin receptors αvβ3 and αvβ5 after pretreatment with the cytokine bFGF in a concentration of 10 ng/ml for 5 days.B. Expression of the integrin receptors αvβ3 and αvβ5 after pretreatment with the cytokine PDGF-BB in a concentration of 10 ng/ml for 5 days.
Figure 2
Figure 2
A. RPE attachment on fibronectin, laminin and collagen IV. The cells were pretreated before the assay with the cyclic integrin antagonist, or the control peptide (10 μg/ml). Untreated RPE cells were used in addition as a standard (ST). B. RPE cell migration induced by PDGF-BB, VEGF and fibronectin. The effect of the cyclic integrin antagonist or the control peptide (cp) on migration is shown. (ST = untreated RPE cells) C. Effect of the cyclic integrin antagonist, (3 ug/ml) or the control peptide on RPE invasion through fibronectin. Cell invasion through fibronectin (F) was stimulated with PDGF-BB (10 ng/ml). Nonspecific effects were excluded by the use of a cyclic control peptide. DMEM without PDGF-BB was used as a control in the assay.
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