A Novel Strategy to Develop Therapeutic Approaches to Prevent Proliferative Vitreoretinopathy

Abstract

Proliferative vitreoretinopathy (PVR) thwarts the repair of rhegmatogenous retinal detachments. Currently, there is no effective prevention for PVR. Platelet-derived growth factor receptor ␣ (PDGFR␣) is associated with PVR in humans and strongly promotes experimental PVR driven by multiple vitreal growth factors outside the PDGF family. We sought to identify vitreal factors required for experimental PVR and to establish a potential approach to prevent PVR. Vitreous was obtained from normal rabbits or those in which PVR was either developing or stabilized. Normal vitreous contained substantial levels of growth factors and cytokines, which changed quantitatively and/or qualitatively as PVR progressed and stabilized. Neutralizing a subset of these agents in rabbit vitreous eliminated their ability to induce PVRrelevant signaling and cellular responses. A single intravitreal injection of neutralizing reagents for this subset prevented experimental PVR. To identify growth factors and cytokines likely driving PVR in humans, we subjected vitreous from patients with or without PVR to a similar series of analyses. This analysis accurately identified those agents required for vitreousinduced contraction of cells from a patient PVR membrane. We conclude that combination therapy encompassing a subset of vitreal growth factors and cytokines is a potential approach to prevent PVR. (Am J Pathol

Defective eyelid leading edge cell migration in C57BL/6-corneal opacity mice with an “eye open at birth” phenotype

“…This may be due to infectious materials in the housing cage and the environment. This phenotype was similar to that observed in Tgfa-deficient mice (Pennock et al, 2011).…”

“…Figure 1C and D), and that their corneas gradually become opaque ( Figure 2B). The phenotype of B6-Co mice was similar to various gene knockout mice, including Egfr, Tgfa, Fgfr2, Map3k1, Hbegf, c-jun, Lgr4, and Rock1 knockouts (Li et al, 2003;Mine et al, 2005;Thumkeo et al, 2005;Kato et al, 2007;Pennock et al, 2011;Martínez-Abadías et al, 2013;Meng et al, 2014;Sanderson et al, 2014). Interestingly, B6-Co eyelids were developmentally similar to that of wild-type B6 mice at E14.5.…”

Vascular Endothelial Growth Factor A Competitively Inhibits Platelet-Derived Growth Factor (PDGF)-Dependent Activation of PDGF Receptor and Subsequent Signaling Events and Cellular Responses

“…Additional experiments verified the MS data; VEGF-A was selectively recovered with the TRAP affinity matrix (Fig. 3b), was present in RV-PVR (6,53), and was heat labile (Fig. 3c and d).…”

“…RV-PVR has a plethora of non-PDGFs, which drive prolonged, indirect activation of PDGFR␣ (Fig. 6a) (44,53). Direct activation of PDGFR␣ antagonizes indirect activation by promoting the rapid clearance of PDGFR␣ from the cell surface and subsequent degradation ( Fig.…”

RasGAP Promotes Autophagy and Thereby Suppresses Platelet-Derived Growth Factor Receptor-Mediated Signaling Events, Cellular Responses, and Pathology

“…RV contains a plethora of growth factors outside the PDGF family (non-PDGFs) and no PDGFs (42,43). Exposing cells to RV directly activates receptor tyrosine kinases, such as ErbB1, ErbB2, IGF-1R, and insulin receptor, and indirectly activates PDGFR␣ (26).…”