Repurposing bortezomib for choroidal neovascularization treatment via antagonizing VEGF-A and PDGF-D mediated signaling.

Abstract

Neovascular age-related macular degeneration (neoAMD) is the leading cause of blindness in AMD and manifests as choroidal neovascularization (CNV). Anti-vascular endothelial growth factor (VEGF) therapies are the mainstay treatments but with limited efficacy and cause detrimental effects on the retina after long-term application. These disadvantages warrant alternative strategy. Herein, we examined the effect on CNV by intravitreal injection of bortezomib, a reversible proteasome inhibitor, and further dissected the mechanism. Krypton red Laser was used to create CNV model in mice. The angiogenesis volume was assessed in choroidal flat-mount with isolectin GS-IB4 labeling and the leakage was examined with fluorescein fundus angiography. Injection of Borsub inhibited angiogenesis in the CNV model which was dose-dependent; the injection significantly inhibited leakage as well. Furthermore, Borsub injection reduced the contents of VEGF-A, macrophage chemotactic factor 1 (MCP-1), and platelet-derived growth factor (PDGF)-D but not PDGF-B, examined by enzyme-linked immunosorbent assay, in choroid/retinal pigment epithelium (RPE) tissue. These injections also reduced phospho-VEGFR-2 and phospho-PDGFRβ in choroid/RPE tissue examined by immunoblotting. Moreover, Borsub inhibited the recruitment of mural cells or macrophages to laser-injured spots. Injection of Borsub indicated negative effect on scotopic and photopic responses recorded by electroretinogram. Altogether, intravitreal injection of Borsub significantly reduced CNV by antagonizing VEGF-A/Flk-1 and PDGF-D/PDGFRβ pathways without impacting electroretinography parameters. Thus, Borsub may offer an invaluable therapy for the prevention and treatment of neoAMD.

• Authors: Yimei Liu, Meiling Feng, Jingjing Cai, Shifeng Li, Xufeng Dai, Ge Shan, Shengzhou Wu
• Journal: Experimental eye research (Exp Eye Res) Vol. 204 Pg. 108446 (03 2021) ISSN: 1096-0007 [Electronic] England
• PMID: 33476605 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Ltd. All rights reserved.

Chemical References

• Angiogenesis Inhibitors
• Antineoplastic Agents
• Ccl2 protein, mouse
• Chemokine CCL2
• Lymphokines
• Pdgfd protein, mouse
• Platelet-Derived Growth Factor
• Vascular Endothelial Growth Factor A
• vascular endothelial growth factor A, mouse
• Bortezomib

Topics

• Angiogenesis Inhibitors (therapeutic use)
• Animals
• Antineoplastic Agents (therapeutic use)
• Blotting, Western
• Bortezomib (therapeutic use)
• Chemokine CCL2 (antagonists & inhibitors, metabolism)
• Choroidal Neovascularization (drug therapy, metabolism, physiopathology)
• Disease Models, Animal
• Drug Repositioning
• Electroretinography (drug effects)
• Enzyme-Linked Immunosorbent Assay
• Fluorescein Angiography
• In Situ Nick-End Labeling
• Intravitreal Injections
• Lymphokines (antagonists & inhibitors, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Microscopy, Confocal
• Platelet-Derived Growth Factor (antagonists & inhibitors, metabolism)
• Signal Transduction (drug effects)
• Vascular Endothelial Growth Factor A (antagonists & inhibitors, metabolism)