SUMOylation is a Translatable Target in Hypoxic MNPs Regulating Retinal Vasculopathy

Area of Science:

• Ophthalmology
• Immunology
• Molecular Biology

Background:

• Retinal vasculopathies are a major health concern, with anti-VEGF therapy showing limited efficacy and potential risks.
• Neurovascular unit uncoupling contributes to neovascularization, but the role of immune components is not well understood.

Purpose of the Study:

• To investigate the role of SUMOylation in macrophage-mediated pro-angiogenic capacity.
• To explore the potential of inhibiting UBC9 as a therapeutic strategy for retinal vascular diseases, alone and in combination with anti-VEGF therapy.

Main Methods:

• Investigated SUMOylation modulation of macrophage pro-angiogenic capacity.
• Examined UBC9 expression in diabetic human retinal mononuclear phagocytes (MNPs).
• Assessed the effects of UBC9 genetic ablation and siRNA-liposomes in preclinical models of retinal vascular disease.

Main Results:

• Diabetic MNPs overexpress UBC9, and its genetic ablation compromises MNP-endothelial cell crosstalk by altering Vegfa splicing isoforms.
• Hypoxia induces FUS SUMOylation, enhancing FUS binding to Vegfa 3'UTR, leading to decreased VEGFA production.
• Ubc9 siRNA-liposomes alleviated retinal vascular leakage and choroidal neovascularization, showing synergistic effects with anti-VEGF therapy.

Conclusions:

• SUMOylation regulates macrophage pro-angiogenic capacity, with UBC9 inhibition showing therapeutic potential.
• Targeting the MNP-endothelial cell interplay via UBC9 modulation offers a novel approach for treating retinal vascular diseases.