title: Quantitative Proteomics Reveals β2 Integrin-mediated Cytoskeletal Rearrangement in Vascular Endothelial Growth Factor (VEGF)-induced Retinal Vascular Hyperpermeability.
abstract: Retinal vascular hyperpermeability causes macular edema, leading to visual deterioration in retinal diseases such as diabetic retinopathy and retinal vascular occlusion. Dysregulation of junction integrity between endothelial cells by vascular endothelial growth factor (VEGF) was shown to cause retinal vascular hyperpermeability. Accordingly, anti-VEGF agents have been used to treat retinal vascular hyperpermeability. However, they can confer potential toxicity through their deleterious effects on maintenance and survival of neuronal and endothelial cells in the retina. Thus, it is important to identify novel therapeutic targets for retinal vascular hyperpermeability other than VEGF. Here, we prepared murine retinas showing VEGF-induced vascular leakage from superficial retinal vascular plexus and prevention of VEGF-induced leakage by anti-VEGF antibody treatment. We then performed comprehensive proteome profiling of these samples and identified retinal proteins for which abundances were differentially expressed by VEGF, but such alterations were inhibited by anti-VEGF antibody. Functional enrichment and network analyses of these proteins revealed the β2 integrin pathway, which can prevent dysregulation of junction integrity between endothelial cells through cytoskeletal rearrangement, as a potential therapeutic target for retinal vascular hyperpermeability. Finally, we experimentally demonstrated that inhibition of the β2 integrin pathway salvaged VEGF-induced retinal vascular hyperpermeability, supporting its validity as an alternative therapeutic target to anti-VEGF agents.
authors.affiliation: From the ‡Fight Against Angiogenesis-related Blindness Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul 03080, Korea; §Department of Biomedical Sciences and Protein Metabolism Medical Research Center, College of Medicine, Seoul National University, Seoul 03080, Korea;
authors.forename: Dong Hyun
authors.initials: DH
authors.lastname: Jo
authors.affiliation: ‖Department of Chemistry, Research Institute for Natural Sciences, Korea University, Seoul 02841, Korea;
authors.forename: Jingi
authors.initials: J
authors.lastname: Bae
authors.affiliation: **Department of New Biology and Center for Plant Aging Research, Institute for Basic Science, Daegu Gyeongbuk Institute of Science and Technology, Daegu 42988, Korea; and.
authors.forename: Sehyun
authors.initials: S
authors.lastname: Chae
authors.affiliation: From the ‡Fight Against Angiogenesis-related Blindness Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul 03080, Korea;
authors.forename: Jin Hyoung
authors.initials: JH
authors.lastname: Kim
authors.affiliation: ‖Department of Chemistry, Research Institute for Natural Sciences, Korea University, Seoul 02841, Korea;
authors.forename: Jong-Hee
authors.initials: JH
authors.lastname: Han
authors.affiliation: **Department of New Biology and Center for Plant Aging Research, Institute for Basic Science, Daegu Gyeongbuk Institute of Science and Technology, Daegu 42988, Korea; and steph25@snu.ac.kr sw_lee@korea.ac.kr dhwang@dgist.ac.kr.
authors.forename: Daehee
authors.initials: D
authors.lastname: Hwang
authors.affiliation: ‖Department of Chemistry, Research Institute for Natural Sciences, Korea University, Seoul 02841, Korea; steph25@snu.ac.kr sw_lee@korea.ac.kr dhwang@dgist.ac.kr.
authors.forename: Sang-Won
authors.initials: SW
authors.lastname: Lee
authors.affiliation: From the ‡Fight Against Angiogenesis-related Blindness Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul 03080, Korea; §Department of Biomedical Sciences and Protein Metabolism Medical Research Center, College of Medicine, Seoul National University, Seoul 03080, Korea; §§Department of Ophthalmology, College of Medicine, Seoul National University, Seoul 03080, Korea steph25@snu.ac.kr sw_lee@korea.ac.kr dhwang@dgist.ac.kr.
authors.forename: Jeong Hun
authors.initials: JH
authors.lastname: Kim
mesh_terms: D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000494:pharmacology; D018821:CD18 Antigens / Q000378:metabolism*; D002199:Capillary Permeability; D003599:Cytoskeleton / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D060066:Protein Interaction Maps / Q000187:drug effects; D040901:Proteomics / Q000379:methods*; D012164:Retinal Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D012171:Retinal Vessels / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*
chemical_list: D000906:Antibodies; D018821:CD18 Antigens; D042461:Vascular Endothelial Growth Factor A