title: Vascular endothelial growth factor acts primarily via platelet-derived growth factor receptor α to promote proliferative vitreoretinopathy.
abstract: Proliferative vitreoretinopathy (PVR) is a nonneovascular blinding disease and the leading cause for failure in surgical repair of rhegmatogenous retinal detachments. Once formed, PVR is difficult to treat. Hence, there is an acute interest in developing approaches to prevent PVR. Of the many growth factors and cytokines that accumulate in vitreous as PVR develops, neutralizing vascular endothelial growth factor (VEGF) A has recently been found to prevent PVR in at least one animal model. The goal of this study was to test if Food and Drug Administration-approved agents could protect the eye from PVR in multiple animal models and to further investigate the underlying mechanisms. Neutralizing VEGF with aflibercept (VEGF Trap-Eye) safely and effectively protected rabbits from PVR in multiple models of disease. Furthermore, aflibercept reduced the bioactivity of both experimental and clinical PVR vitreous. Finally, although VEGF could promote some PVR-associated cellular responses via VEGF receptors expressed on the retinal pigment epithelial cells that drive this disease, VEGF's major contribution to vitreal bioactivity occurred via platelet-derived growth factor receptor α. Thus, VEGF promotes PVR by a noncanonical ability to engage platelet-derived growth factor receptor α. These findings indicate that VEGF contributes to nonangiogenic diseases and that anti-VEGF-based therapies may be effective on a wider spectrum of diseases than previously appreciated.
authors.affiliation: The Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts; Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Steven
authors.initials: S
authors.lastname: Pennock
authors.affiliation: The Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts; Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Luis J
authors.initials: LJ
authors.lastname: Haddock
authors.affiliation: The Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts; Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Shizuo
authors.initials: S
authors.lastname: Mukai
authors.affiliation: The Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts; Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts. Electronic address: andrius_kazlauskas@meei.harvard.edu.
authors.forename: Andrius
authors.initials: A
authors.lastname: Kazlauskas
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D011817:Rabbits; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D015398:Signal Transduction / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D018630:Vitreoretinopathy, Proliferative / Q000378:metabolism* / Q000517:prevention & control*
chemical_list: D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; C533178:aflibercept; D020796:Receptor, Platelet-Derived Growth Factor alpha; D040262:Receptors, Vascular Endothelial Growth Factor