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While anti\u2010VEGF therapy situates the first\u2010line treatment for patients, the clinical efficacy is limited by suboptimal response and potential risks raised by long\u2010term high\u2010dosage use. Neurovascular unit uncoupling is recognized as a key mechanism contributing to pathological neovascularization, yet how immune components get involved is less appreciated. Here, it is reported that SUMOylation modulates the pro\u2010angiogenic capacity of macrophage, and inhibition of the SUMO\u2010conjugating enzyme UBC9 synergizes with anti\u2010VEGF therapy in preclinical models. Diabetic human retinal mononuclear phagocytes (MNPs) overexpress UBC9. Genetic ablation of UBC9 in MNPs compromises the crosstalk with endothelial cells by reducing <jats:italic>Vegfa<\/jats:italic> splicing isoforms, including <jats:italic>Vegf120<\/jats:italic>, <jats:italic>Vegf144<\/jats:italic>, <jats:italic>Vegf164<\/jats:italic>, and <jats:italic>Vegf188<\/jats:italic>. Mechanistically, hypoxia facilitates the SUMOylation of fused in sarcoma (FUS) protein at lysine residues K327 and K502. Mutation of the SUMOylation sites enhances FUS binding to the <jats:italic>Vegfa<\/jats:italic> 3\u2032\u2010untranslated region (3\u2032UTR), leading to mRNA destabilization and decreased VEGFA production. Intravitreal administration of anti\u2010VEGF elevates UBC9 whereas Ubc9 siRNA\u2010liposomes alleviates retinal vascular leakage and choroidal neovascularization, and a better therapeutic efficacy is yielded when combining with anti\u2010VEGF therapy. Taken together, this study highlights a novel approach for treating retinal vascular diseases by modulating the MNPs\u2010endothelial cell interplay.<\/jats:p>","DOI":"10.1002\/advs.202503505","type":"journal-article","created":{"date-parts":[[2025,5,31]],"date-time":"2025-05-31T08:55:56Z","timestamp":1748681756000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["SUMOylation is a Translatable Target in Hypoxic MNPs Regulating Retinal Vasculopathy"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1717-4109","authenticated-orcid":false,"given":"Zheng","family":"Zhong","sequence":"first","affiliation":[{"name":"Department of Ophthalmology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology  Wuhan 430030 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangyu","family":"Liang","sequence":"additional","affiliation":[{"name":"Experimental Medicine Center Tongji Hospital Tongji Medical College Huazhong University of Science and Technology  Wuhan 430000 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huimin","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology  Wuhan 430030 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqi","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology  Wuhan 430030 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruohong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology  Wuhan 430030 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohong","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology  Wuhan 430030 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziqing","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology  Wuhan 430030 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yin","family":"Zhao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Otorhinolaryngologic and Ophthalmic Diseases Tongji Hospital Tongji Medical College Huazhong University of Science and Technology  Wuhan 430000 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Sun","sequence":"additional","affiliation":[{"name":"The Center for Biomedical Research NHC Key Laboratory of Respiratory Diseases Tongji Hospital Tongji Medical College Huazhong University of Science and Technology  Wuhan 430000 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7133-4508","authenticated-orcid":false,"given":"Xufang","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology  Wuhan 430030 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,5,31]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1111\/aos.15005"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1136\/bjophthalmol-2019-315199"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaophthalmol.2017.6565"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajo.2018.08.004"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2023.101209"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature25013"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2022.106559"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2112561118"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.93382"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10456-024-09911-1"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-022-00500-y"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2021014267"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-019-2130-z"},{"key":"e_1_2_9_14_1","first-page":"4","volume":"7","author":"Li X.","year":"2021","journal-title":"Sci. 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