The ANGPTL3-integrin α5 axis drives retinal vascular leakage in diabetic retinopathy.

BACKGROUND: Breakdown of the blood-retinal barrier (BRB) is a key driver of diabetic retinopathy (DR). While Angiopoietin-like protein 3 (ANGPTL3) is a clinical predictor of DR, its causal role and mechanism in retinal vascular pathology are unknown. METHODS: This study combined genetic (Angptl3 knockout and overexpression) and pharmacological (intravitreal evinacumab) approaches in streptozotocin-induced diabetic mice to define the in vivo function of ANGPTL3. In vivo assessments included fluorescein angiography and optical coherence tomography for retinal vascular integrity, alongside electron microscopy for ultrastructural analysis of endothelial junctions. Mechanistic investigations involved co-immunoprecipitation to probe the ANGPTL3-integrin α5 interaction, and in vitro permeability assays using human endothelial cells. The therapeutic efficacy of a neutralizing antibody, evinacumab, was subsequently evaluated via intravitreal administration in diabetic mice. RESULTS: ANGPTL3 overexpression exacerbated STZ-induced retinal vascular leakage, increased retinal thickness, and disrupted endothelial junctions. Plasma ANGPTL3 levels were significantly lower in knockout mice and elevated in overexpression mice, with no observed effects on body weight or systemic glucose tolerance. Co-immunoprecipitation assays confirmed a direct interaction between ANGPTL3 and integrin α5. In HUVECs, integrin α5 knockdown attenuated ANGPTL3-induced downregulation of ZO-1 and VE-cadherin expression, thereby preserving endothelial barrier function. In vivo, intravitreal evinacumab reduced vascular leakage and restored junctional protein levels in diabetic mice, without altering body weight or systemic glucose metabolism. CONCLUSIONS: This study identifies a novel mechanism whereby ANGPTL3 disrupts endothelial junctions via integrin α5-dependent pathways, thereby contributing to DR progression. The ANGPTL3-integrin α5 axis represents a promising therapeutic target, with pharmacological inhibition offering a potential strategy to ameliorate diabetic vascular leakage. CLINICAL TRIAL REGISTRATION NUMBER: Not applicable. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-026-07710-4.