Integrating OLINK Proteomics and Single-Cell Analysis Reveals that DCBLD2 Potentiates VEGFA-Driven Angiogenesis in Retinal Detachment with Choroidal Detachment

Rhegmatogenous retinal detachment with choroidal detachment
(RRDCD)
is a severe ophthalmologic condition whose molecular drivers remain
unclear. Here, we integrated Olink proteomics of vitreous fluid from
RRDCD and RRD patients (n = 20 each) with single-cell protein activity
inference to uncover key pathogenic mechanisms. Proteomic analysis
identified 110 statistically significant differentially expressed
proteins (DEPs) revealing a significant upregulation of pro-inflammatory
pathways, including TNF-α/NF-κB signaling in RRDCD. This
multimodal analysis pinpointed DCBLD2 and VEGFA as central cooperating
regulators. Functional validation in choroidal endothelial cells confirmed
that DCBLD2 and VEGFA act synergistically to enhanced cell proliferation,
migration, and angiogenic tube formation. Mechanistically, we demonstrate
that DCBLD2 potentiates VEGFA-driven effects by increasing VEGFR2
phosphorylation and activating its downstream AKT and ERK1/2 signaling
cascades. Our study reveals a novel synergistic axis where DCBLD2
amplifies VEGFA/VEGFR2 signaling to drive the pathological angiogenesis
and inflammation characteristic of RRDCD. This work not only deepens
our understanding of RRDCD pathogenesis but also establishes DCBLD2
and VEGFA as promising cooperative biomarkers and therapeutic targets
for future clinical intervention.