Antagonism of PDGF-BB suppresses subretinal neovascularization and enhances the effects of blocking VEGF-A

Aling Dong, Christopher Seidel, Daniel Snell, Savira Ekawardhani, Julia K.J. Ahlskog, Michael Baumann, Jikui Shen, Takeshi Iwase, Jing Tian, Rebecca Stevens, Sean F. Hackett, Michael T. Stumpp, Peter A. Campochiaro

Research output: Contribution to journalArticle

Abstract

Hypoxia-inducible factor-1 (HIF-1) plays an important role in retinal and subretinal neovascularization (NV). Increased levels of HIF-1 cause increased expression of vascular endothelial growth factor (VEGF-A) and current therapies for ocular NV focus on neutralizing VEGF-A, but there is mounting evidence that other HIF-1-responsive gene products may also participate. In this study, we tested the effect of a designed ankyrin repeat protein (DARPin) that selectively binds and antagonizes the hypoxia-regulated gene product PDGF-BB in three models of subretinal NV (relevant to neovascular age-related macular degeneration) and compared its effects to a DARPin that selectively antagonizes VEGF-A. Daily intraperitoneal injections of 10 mg/kg of the anti-PDGF-BB DARPin or 1 mg/kg of the anti-VEGF DARPin significantly suppressed subretinal NV from laser-induced rupture of Bruch's membrane. Injections of 1 mg/kg/day of the anti-PDGF-BB DARPin had no significant effect, but when combined with 1 mg/kg/day of the anti-VEGF-A DARPin there was greater suppression than injection of the anti-VEGF-A DARPin alone. In Vldlr -/- mice which spontaneously develop subretinal NV, intraocular injection of 1.85 μg of anti-PDGF-BB or anti-VEGF-A DARPin caused significant suppression of NV and when combined there was greater suppression than with either alone. The two DARPins also showed an additive effect in Tet/opsin/VEGF double transgenic mice, a particularly severe model of subretinal NV and exudative retinal detachment. In addition, intraocular injection of 1.85 μg of anti-PDGF-BB DARPin strongly suppressed ischemia-induced retinal NV, which is relevant to proliferative diabetic retinopathy and retinopathy of prematurity. These data demonstrate that PDGF-BB is another hypoxia-regulated gene product that along with VEGF-A contributes to ocular NV and suppression of both provides an additive effect.

Original languageEnglish (US)
Pages (from-to)553-562
Number of pages10
JournalAngiogenesis
Volume17
Issue number3
DOIs
StatePublished - Jul 2014

Keywords

  • Age-related macular degeneration
  • DARPin
  • Diabetic retinopathy
  • HIF-1

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cancer Research

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    Dong, A., Seidel, C., Snell, D., Ekawardhani, S., Ahlskog, J. K. J., Baumann, M., Shen, J., Iwase, T., Tian, J., Stevens, R., Hackett, S. F., Stumpp, M. T., & Campochiaro, P. A. (2014). Antagonism of PDGF-BB suppresses subretinal neovascularization and enhances the effects of blocking VEGF-A. Angiogenesis, 17(3), 553-562. https://doi.org/10.1007/s10456-013-9402-5