PMID- 33476605 OWN - NLM STAT- MEDLINE DCOM- 20210827 LR - 20210827 IS - 1096-0007 (Electronic) IS - 0014-4835 (Linking) VI - 204 DP - 2021 Mar TI - Repurposing bortezomib for choroidal neovascularization treatment via antagonizing VEGF-A and PDGF-D mediated signaling. PG - 108446 LID - S0014-4835(21)00011-7 [pii] LID - 10.1016/j.exer.2021.108446 [doi] AB - 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 Bor(sub) inhibited angiogenesis in the CNV model which was dose-dependent; the injection significantly inhibited leakage as well. Furthermore, Bor(sub) 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-PDGFRbeta in choroid/RPE tissue examined by immunoblotting. Moreover, Bor(sub) inhibited the recruitment of mural cells or macrophages to laser-injured spots. Injection of Bor(sub) indicated negative effect on scotopic and photopic responses recorded by electroretinogram. Altogether, intravitreal injection of Bor(sub) significantly reduced CNV by antagonizing VEGF-A/Flk-1 and PDGF-D/PDGFRbeta pathways without impacting electroretinography parameters. Thus, Bor(sub) may offer an invaluable therapy for the prevention and treatment of neoAMD. CI - Copyright (c) 2021 Elsevier Ltd. All rights reserved. FAU - Liu, Yimei AU - Liu Y AD - School of Optometry and Ophthalmology and the Eye Hospital, Wenzhou Medical University, PR China; State Key Laboratory of Optometry, Ophthalmology, and Visual Science, 270 Xueyuan Road, Wenzhou, Zhejiang, 325003, PR China. FAU - Feng, Meiling AU - Feng M AD - School of Optometry and Ophthalmology and the Eye Hospital, Wenzhou Medical University, PR China; State Key Laboratory of Optometry, Ophthalmology, and Visual Science, 270 Xueyuan Road, Wenzhou, Zhejiang, 325003, PR China. FAU - Cai, Jingjing AU - Cai J AD - School of Optometry and Ophthalmology and the Eye Hospital, Wenzhou Medical University, PR China; State Key Laboratory of Optometry, Ophthalmology, and Visual Science, 270 Xueyuan Road, Wenzhou, Zhejiang, 325003, PR China. FAU - Li, Shifeng AU - Li S AD - Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, PR China. FAU - Dai, Xufeng AU - Dai X AD - School of Optometry and Ophthalmology and the Eye Hospital, Wenzhou Medical University, PR China; State Key Laboratory of Optometry, Ophthalmology, and Visual Science, 270 Xueyuan Road, Wenzhou, Zhejiang, 325003, PR China. FAU - Shan, Ge AU - Shan G AD - CAS Key Laboratory of Innate Immunity and Chronic Disease, CAS Center for Excellence in Molecular Cell Science, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui Province, 230027, China. FAU - Wu, Shengzhou AU - Wu S AD - School of Optometry and Ophthalmology and the Eye Hospital, Wenzhou Medical University, PR China; State Key Laboratory of Optometry, Ophthalmology, and Visual Science, 270 Xueyuan Road, Wenzhou, Zhejiang, 325003, PR China. Electronic address: wszlab@mail.eye.ac.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210118 PL - England TA - Exp Eye Res JT - Experimental eye research JID - 0370707 RN - 0 (Angiogenesis Inhibitors) RN - 0 (Antineoplastic Agents) RN - 0 (Ccl2 protein, mouse) RN - 0 (Chemokine CCL2) RN - 0 (Lymphokines) RN - 0 (Pdgfd protein, mouse) RN - 0 (Platelet-Derived Growth Factor) RN - 0 (Vascular Endothelial Growth Factor A) RN - 0 (vascular endothelial growth factor A, mouse) RN - 69G8BD63PP (Bortezomib) SB - IM MH - Angiogenesis Inhibitors/*therapeutic use MH - Animals MH - Antineoplastic Agents/*therapeutic use MH - Blotting, Western MH - Bortezomib/*therapeutic use MH - Chemokine CCL2/antagonists & inhibitors/metabolism MH - Choroidal Neovascularization/*drug therapy/metabolism/physiopathology MH - *Disease Models, Animal MH - Drug Repositioning MH - Electroretinography/drug effects MH - Enzyme-Linked Immunosorbent Assay MH - Fluorescein Angiography MH - In Situ Nick-End Labeling MH - Intravitreal Injections MH - Lymphokines/*antagonists & inhibitors/metabolism MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Microscopy, Confocal MH - Platelet-Derived Growth Factor/*antagonists & inhibitors/metabolism MH - Signal Transduction/drug effects MH - Vascular Endothelial Growth Factor A/*antagonists & inhibitors/metabolism OTO - NOTNLM OT - Age-related macular degeneration OT - Choroidal neovascularization OT - Fluorescein fundus angiography OT - Platelet-derived growth factor OT - Proteasome inhibitor OT - Vascular endothelial growth factor EDAT- 2021/01/22 06:00 MHDA- 2021/08/28 06:00 CRDT- 2021/01/21 20:10 PHST- 2020/06/25 00:00 [received] PHST- 2021/01/06 00:00 [revised] PHST- 2021/01/11 00:00 [accepted] PHST- 2021/01/22 06:00 [pubmed] PHST- 2021/08/28 06:00 [medline] PHST- 2021/01/21 20:10 [entrez] AID - S0014-4835(21)00011-7 [pii] AID - 10.1016/j.exer.2021.108446 [doi] PST - ppublish SO - Exp Eye Res. 2021 Mar;204:108446. doi: 10.1016/j.exer.2021.108446. Epub 2021 Jan 18.