SUMOylation is a Translatable Target in Hypoxic MNPs Regulating Retinal Vasculopathy
Abstract Retinal vasculopathies pose a devastating threat to human health. While anti‐VEGF therapy situates the first‐line treatment for patients, the clinical efficacy is limited by suboptimal response and potential risks raised by long‐term high‐dosage use. Neurovascular unit uncoupling is recogni...
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| Format: | Article |
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Wiley
2025-08-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202503505 |
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| author | Zheng Zhong Guangyu Liang Huimin Yu Jiaqi Li Ruohong Wang Xiaohong Ma Ziqing Zhou Yin Zhao Fei Sun Xufang Sun |
| author_facet | Zheng Zhong Guangyu Liang Huimin Yu Jiaqi Li Ruohong Wang Xiaohong Ma Ziqing Zhou Yin Zhao Fei Sun Xufang Sun |
| author_sort | Zheng Zhong |
| collection | DOAJ |
| description | Abstract Retinal vasculopathies pose a devastating threat to human health. While anti‐VEGF therapy situates the first‐line treatment for patients, the clinical efficacy is limited by suboptimal response and potential risks raised by long‐term high‐dosage 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‐angiogenic capacity of macrophage, and inhibition of the SUMO‐conjugating enzyme UBC9 synergizes with anti‐VEGF 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 Vegfa splicing isoforms, including Vegf120, Vegf144, Vegf164, and Vegf188. 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 Vegfa 3′‐untranslated region (3′UTR), leading to mRNA destabilization and decreased VEGFA production. Intravitreal administration of anti‐VEGF elevates UBC9 whereas Ubc9 siRNA‐liposomes alleviates retinal vascular leakage and choroidal neovascularization, and a better therapeutic efficacy is yielded when combining with anti‐VEGF therapy. Taken together, this study highlights a novel approach for treating retinal vascular diseases by modulating the MNPs‐endothelial cell interplay. |
| format | Article |
| id | doaj-art-2fcea37c685d438a8c1c6ec3cfdcfa30 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-2fcea37c685d438a8c1c6ec3cfdcfa302025-08-23T14:12:39ZengWileyAdvanced Science2198-38442025-08-011231n/an/a10.1002/advs.202503505SUMOylation is a Translatable Target in Hypoxic MNPs Regulating Retinal VasculopathyZheng Zhong0Guangyu Liang1Huimin Yu2Jiaqi Li3Ruohong Wang4Xiaohong Ma5Ziqing Zhou6Yin Zhao7Fei Sun8Xufang Sun9Department of Ophthalmology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 ChinaExperimental Medicine Center Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430000 ChinaDepartment of Ophthalmology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 ChinaDepartment of Ophthalmology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 ChinaDepartment of Ophthalmology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 ChinaDepartment of Ophthalmology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 ChinaDepartment of Ophthalmology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 ChinaKey Laboratory of Otorhinolaryngologic and Ophthalmic Diseases Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430000 ChinaThe Center for Biomedical Research NHC Key Laboratory of Respiratory Diseases Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430000 ChinaDepartment of Ophthalmology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 ChinaAbstract Retinal vasculopathies pose a devastating threat to human health. While anti‐VEGF therapy situates the first‐line treatment for patients, the clinical efficacy is limited by suboptimal response and potential risks raised by long‐term high‐dosage 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‐angiogenic capacity of macrophage, and inhibition of the SUMO‐conjugating enzyme UBC9 synergizes with anti‐VEGF 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 Vegfa splicing isoforms, including Vegf120, Vegf144, Vegf164, and Vegf188. 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 Vegfa 3′‐untranslated region (3′UTR), leading to mRNA destabilization and decreased VEGFA production. Intravitreal administration of anti‐VEGF elevates UBC9 whereas Ubc9 siRNA‐liposomes alleviates retinal vascular leakage and choroidal neovascularization, and a better therapeutic efficacy is yielded when combining with anti‐VEGF therapy. Taken together, this study highlights a novel approach for treating retinal vascular diseases by modulating the MNPs‐endothelial cell interplay.https://doi.org/10.1002/advs.202503505pro‐angiogenic MNPsretinal vasculopathiesSUMOylationUBC9 |
| spellingShingle | Zheng Zhong Guangyu Liang Huimin Yu Jiaqi Li Ruohong Wang Xiaohong Ma Ziqing Zhou Yin Zhao Fei Sun Xufang Sun SUMOylation is a Translatable Target in Hypoxic MNPs Regulating Retinal Vasculopathy Advanced Science pro‐angiogenic MNPs retinal vasculopathies SUMOylation UBC9 |
| title | SUMOylation is a Translatable Target in Hypoxic MNPs Regulating Retinal Vasculopathy |
| title_full | SUMOylation is a Translatable Target in Hypoxic MNPs Regulating Retinal Vasculopathy |
| title_fullStr | SUMOylation is a Translatable Target in Hypoxic MNPs Regulating Retinal Vasculopathy |
| title_full_unstemmed | SUMOylation is a Translatable Target in Hypoxic MNPs Regulating Retinal Vasculopathy |
| title_short | SUMOylation is a Translatable Target in Hypoxic MNPs Regulating Retinal Vasculopathy |
| title_sort | sumoylation is a translatable target in hypoxic mnps regulating retinal vasculopathy |
| topic | pro‐angiogenic MNPs retinal vasculopathies SUMOylation UBC9 |
| url | https://doi.org/10.1002/advs.202503505 |
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