Biglycan stimulates retinal pathological angiogenesis via up-regulation of CXCL12 expression in pericytes

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. In this study, we investigated the role of extracellular matrix (ECM) protein biglycan (BGN) in PA using an oxygen-induced retinopathy (OIR) mouse model, along with hypoxia (1% O₂) conditions for incubating pericytes and endothelial cells in vitro. We found a significant upregulation of Bgn in the retinas of OIR mice. Intravitreal injection of Bgn-specific small interfering RNA (siRNA) in OIR mice at postnatal day 12 (P12) effectively curbed retinal PA at P17. Using cultured cells, we found that BGN expression in pericytes was highly sensitive to hypoxic stimulation compared to endothelial cells. We further showed that 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, our 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.