Intraocular VEGF deprivation induces degeneration and fibrogenic response in retina.

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.

• Authors: Meichun Xiao, Yang Liu, Lingyu Wang, Jian Liang, Tianjun Wang, Yuanqi Zhai, Yafang Wang, Shu Liu, Wenjia Liu, Xueting Luo, Fenghua Wang, Xiaodong Sun
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 33 Issue 12 Pg. 13920-13934 (12 2019) ISSN: 1530-6860 [Electronic] United States
• PMID: 31648566 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• 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)