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Originally published In Press as doi:10.1167/iovs.08-3042 on March 25, 2009
 (Investigative Ophthalmology and Visual Science. 2009;50:3394-3403.)
© 2009 by The Association for Research in Vision and Ophthalmology, Inc.
doi:10.1167/iovs.08-3042
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Growth Factors Outside the PDGF Family Drive Experimental PVR

Hetian Lei,1 Gisela Velez,1 Peter Hovland,1,2 Tatsuo Hirose,1,2 Debra Gilbertson,3 and Andrius Kazlauskas1

1From the Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts; 2Schepens Retina Associates Foundation, Boston, Massachusetts; and 3ZymoGenetics, Seattle, Washington.

PURPOSE. Proliferative vitreoretinopathy (PVR) is a recurring and problematic disease for which there is no pharmacologic treatment. Platelet-derived growth factor (PDGF) in the vitreous is associated with experimental and clinical PVR. Furthermore, PDGF receptors (PDGFRs) are present and activated in epiretinal membranes of patient donors, and they are essential for experimental PVR. These observations suggest that PVR arises at least in part from PDGF/PDGFR-driven events. The goal of this study was to determine whether PDGFs were a potential therapeutic target for PVR.

METHODS. Experimental PVR was induced in rabbits by injecting fibroblasts. Vitreous specimens were collected from experimental rabbits or from patients undergoing vitrectomy to repair retinal detachment. A neutralizing PDGF antibody and a PDGF Trap were tested for their ability to prevent experimental PVR. Activation of PDGFR was monitored by antiphosphotyrosine Western blot analysis of immunoprecipitated PDGFRs. Contraction of collagen gels was monitored in vitro.

RESULTS. Neutralizing vitreal PDGFs did not effectively attenuate PVR, even though the reagents used potently blocked PDGF-dependent activation of the PDGF {alpha} receptor (PDGFR{alpha}). Vitreal growth factors outside the PDGF family modestly activated PDGFR{alpha} and appeared to do so without engaging the ligand-binding domain of PDGFR{alpha}. This indirect route to activate PDGFR{alpha} had profound functional consequences. It promoted the contraction of collagen gels and appeared sufficient to drive experimental PVR.

CONCLUSIONS. Although PDGF appears to be a poor therapeutic target, PDGFR{alpha} is particularly attractive because it can be activated by a much larger spectrum of vitreal growth factors than previously appreciated.




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