Intraocular VEGF deprivation induces degeneration and fibrogenic response in retina

FASEB J. 2019 Dec;33(12):13920-13934. doi: 10.1096/fj.201901283RR. Epub 2019 Oct 23.

Abstract

VEGF is a critical driver of ocular neovascularization under disease conditions. Current therapeutic strategies rely on intraocular delivery of VEGF-antagonizing reagents, which results in sustained suppression of pathogenic vascularization. Although significant advancement has been achieved in VEGF antagonism, substantial adverse effects have been reported in retrospective clinical studies. To study mechanisms for VEGF antagonism-associated adverse effects in visual system, we intravitreally delivered recombinant adeno-associated virus-mediated expression of soluble Fms-related tyrosine kinase-1 (rAAV.sFLT-1), the extracellular domain of VEGF receptor, and analyzed the morphology and functions of retinal tissue. Here, we confirmed that intraocular VEGF antagonism induced retinal degeneration and gliosis. The functional deficit in retinal response to visual stimulation was also demonstrated in rAAV.sFLT-1-treated eyes by electroretinogram. Moreover, high-throughput RNA sequencing analysis suggests that VEGF antagonism activates retinal degeneration, inflammation, and other adverse effects. Taken together, our findings have shed light on pathogenic mechanisms for VEGF antagonism-associated adverse effects and potential therapeutic targets.-Xiao, M., Liu, Y., Wang, L., Liang, J., Wang, T., Zhai, Y., Wang, Y., Liu, S., Liu, W., Luo, X., Wang, F., Sun, X. Intraocular VEGF deprivation induces degeneration and fibrogenic response in retina.

Keywords: AMD; RNA-Seq; fibrosis; retinal degeneration; sFLT-1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Choroidal Neovascularization / metabolism
  • Dependovirus / metabolism
  • Genetic Vectors / metabolism
  • Gliosis / metabolism
  • HEK293 Cells
  • Humans
  • Inflammation / metabolism
  • Mice
  • Retina
  • Retinal Degeneration / metabolism
  • Retrospective Studies
  • Vascular Endothelial Growth Factor A / metabolism*
  • Vascular Endothelial Growth Factor Receptor-1 / metabolism

Substances

  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factor Receptor-1