Growth Factors Outside the PDGF Family Drive Experimental PVR

Proliferative vitreoretinopathy (PVR) occurs as a complication in 3.9% to 13.7% of patients undergoing surgery to reattach a detached retina.1,2 This is a blinding disease in which the retina re-detaches because of the contraction of a fibroproliferative membrane that forms on the surface of the retina.3-6 Vitreal growth factors are thought to promote formation and contraction of the membrane, which is populated by several cell types, including retinal pigment epithelial cells, fibroblasts, glial cells, and macrophages.7-11 Platelet-derived growth factor (PDGF) is among the long list of vitreal growth factors implicated in contributing to PVR.9,12-25 Additional evidence for the role of PDGF/PDGFR in PVR are the observations that cells within the fibroproliferative membrane isolated from patient donors express PDGF and PDGFRs and that the PDGFRs are activated.9,26,27 Furthermore, in an experimental model of PVR, functional PDGFRs are a prerequisite for disease formation.28-30 Given that key components of PVR (proliferation of myofibroblasts and increased synthesis of extracellular matrix) are common to fibrosis in other organs, it is likely that the insights gleaned from the study of any one of these settings will be at least in part applicable to the other pathologic settings. The most common animal models of PVR involve the injection of cells into the vitreous and subsequent observation of the formation of a membrane, which contracts and thereby induces retinal detachment.31 Several groups have found that PVR is substantially attenuated if PDGFRs of the injected cells were missing or inhibited.28-30 The source of PDGF to activate these receptors appears to initially be from the coinjected, platelet-rich plasma. At later time points, there are high levels of PDGF-C in the vitreous, coming at least in part from the injected cells that naturally produce this isoform of PDGF.15 The presence of PDGF-C in the vitreous of rabbits mirrored the clinical situation. PDGF-C was observed in the vitreous of most patients with PVR, but no PDGF-C was detected in most patients without PVR.15 Taken together, these findings suggest that neutralizing PDGF-C could prevent experimental PVR and could be a potential therapy for patients with PVR. The PDGF family is composed of five ligands that assemble dimeric receptors consisting of homodimer or heterodimer combinations of the two PDGF receptor subunits.32-34 There are several mechanisms by which PDGFRs are activated (i.e., undergo tyrosine phosphorylation) and thereby initiate intra-cellular signaling events that culminate in various cellular responses. The most extensively studied mechanism involves PDGF-dependent dimerization of receptor subunits that increases the receptor's intrinsic kinase activity and results in extensive autophosphorylation.35,36 Certain agonists of G protein–coupled receptors, autoantibodies in the blood of patients with scleroderma, and certain agents within the bone marrow (but are probably not PDGFs) also promote tyrosine phosphorylation of PDGFR.37-44 Finally, signaling events induced by polypeptide growth factors outside the PDGF family (non-PDGFs) are greater in cells that express PDGFRs than in nonexpressing cells,45 suggesting that non-PDGFs are capable of engaging PDGFRs. Together these data indicate that activation of PDGFRs is not restricted to the direct PDGF-dependent route, suggesting that PDGFRs may act independently of PDGFs to contribute to cellular responses and even disease manifestation. While investigating the role of PDGF/PDGFR in PVR, we discovered that experimental PVR was more dependent on PDGFRα than the PDGF isoforms that activate this receptor. Moreover, non-PDGFs activated PDGFRα—that is, they increased tyrosine phosphorylation of PDGFRα and potentiated contraction of collagen gels. Finally, activation of PDGFRα by non-PDGFs was sufficient to induce experimental PVR.