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 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.