BGN stimulates retinal pathological angiogenesis via up-regulation of CXCL12 expression in pericytes (human)

Retinal pathological angiogenesis (PA) is a common hallmark in proliferative retinopathies, including age-related macular degeneration (AMD), proliferative diabetic retinopathy (PDR), and retinopathy of prematurity (ROP). The mechanisms underlying PA is complex and incompletely understood. Using oxygen-induced retinopathy (OIR) mouse as a model, the role of extracellular matrix (ECM) protein biglycan (BGN) in PA was studied. Significant upregulation of BGN in the retina of OIR mice and in neovascular proliferative membranes of PDR patients was found. The reduction of BGN expression by Bgn-specific small interfering RNA (siRNA) effectively diminished retinal PA in OIR mouse. Subsequent analysis of the mouse OIR retinal single-cell RNA sequencing data from the Gene Expression Omnibus dataset (GSE150703) suggested pericyte as a source of BGN. This was verified using cultured retinal capillary pericytes. BGN expression in pericytes was highly sensitive to hypoxic stimulation. BGN stimulated retinal PA via the upregulation of C-X-C motif chemokine ligand 12 (CXCL12). Inhibition of the CXCL12-CXCR4 axis effectively diminished PA in OIR mouse. In conclusion, this study demonstrated the stimulatory role of BGN in retinal PA, identified the link between BGN and CXCL12 expression, and further highlighted the role of pericytes in retinal PA.