Quantitative proteomic analysis of vitreous from patients with proliferative diabetic retinopathy (PDR) using SWATH-MS

ABSTRACT: Pathological neovascularization and vascular leakage are central drivers of many sight- threatening diseases. While strategies targeting vascular endothelial growth factor (VEGF) have transformed clinical outcomes, a substantial proportion of patients do not benefit from the treatment, partially attributed to compensatory activation of alternative angiogenic pathways. Two independent vitreous proteomics studies in patients with proliferative diabetic retinopathy (PDR) revealed a significant reduction in the level of Frizzled-related Protein (FRZB), a finding mirrored in preclinical models of ocular angiogenesis. Loss of Frzb in mice exacerbated ocular angiogenesis, while therapeutic delivery of Fc-FRZB recombination protein or its functional domain netrin-related motif (NTR) potently suppressed and reversed ocular angiogenesis across various preclinical models. Notably, Fc-NTR synergized with Aflibercept, suggesting its potential as a combination therapy. Mechanistically, FRZB doesn’t modulate Wnt signalling in retinal microvascular endothelial cells. Instead, it binds directly to Caveolin-1 (CAV1), inhibits its phosphorylation, promotes surface retention of the TGFβ type I receptor ALK5, and ultimately leads to cytoplasmic accumulation of phosphorylated Smad2/3. Intriguingly, retinal endothelial cells expressing a phosphomimetic CAV1 mutant (Y42D) at a previously uncharacterized site, Tyr42, were resistant to FRZB’s anti-angiogenic effects, establishing a novel CAV1–TGFβ signalling axis as the molecular basis of FRZB’s action. Collectively, these findings define FRZB as a novel suppressor of ocular angiogenesis, uncover a previously unknown mechanism of TGFβ regulation, and establish Fc-NTR as a promising therapeutic candidate for treating ocular angiogenic diseases.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Vitreous Humor

SUBMITTER: Lei Zhou  

LAB HEAD: Lei ZHOU

PROVIDER: PXD073005 | Pride | 2026-03-13

REPOSITORIES: Pride