Role of angiopoietin-like 4 in neovascularization associated with retinopathy of prematurity

Abstract

To elucidate the mechanisms of angiopoietin-like 4 (ANGTPL4) in neovascularization (NV) in retinopathy of prematurity (ROP). We compared ANGPTL4 expression levels of aqueous humour and vitreous fluid samples in infants with acute-phase ROP and control group. ANGPTL4^−/− mice and WT mice were used to constructed oxygen-induced retinopathy (OIR) mouse models, with retinal tissues collected on postnatal days 12 (P12), 15 (P15) and 17 (P17). Analysis of retinal vessels and transcriptomics were performed to explore the role of ANGTPL4 in NV. The results showed ANGPTL4 level was significantly higher in the aqueous humour and vitreous fluid of children with ROP than that of control group. At P15 and P17, the vascular indices in the ANGPTL4^−/−-CON group were lower than those in the WT-CON group. The central non-perfused area of the retina and number of neovascular nuclei were also smaller in the ANGPTL4^−/−-OIR group than in the WT-OIR group. Immunofluorescence results showed the overexpression of ANGPTL4 protein in the WT-OIR group than in the WT-CON group, especially at P17. Furthermore, extracellular matrix (ECM) organisation was one of the key involved pathways based on gene ontology (GO) enrichment analyses. ANGPTL4 was one of the core genes involved in ECM organization, and neuralized E3 ubiquitin protein ligase 1B (NEURL1B), cd36 Molecule (CD36), matrix metallopeptidase 3 (MMP3) and collagen type III alpha 1 chain (COL3A1) were the first nodes interacting with ANGPTL4.In conclusion, ANGPTL4 is involved in the pathological NV by regulating NEURL1B, CD36, MMP3, and COL3A1. Thus, ANGPTL4 is a potential therapeutic target for ROP.