Pathogenesis of Neovascular Glaucoma in Diabetic Retinopathy: A Review

Neovascular glaucoma (NVG) secondary to diabetic retinopathy (DR) is a severe complication driven by ischemia-induced angiogenesis. Current evidence indicates that the pathogenesis begins with retinal hypoxia caused by hyperglycemia-induced capillary occlusion, which stabilizes hypoxia-inducible factor-1α (HIF-1α) and upregulates vascular endothelial growth factor (VEGF). VEGF-A and placental growth factor (PlGF) drive abnormal angiogenesis in the retina, iris, and anterior chamber angle. Downregulation of endogenous inhibitors such as pigment epithelium-derived factor (PEDF) may exacerbate this process. Concomitant inflammation mediated by cytokines including interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), followed by transforming growth factor-β (TGF-β)-induced fibrotic angle closure, collectively leads to refractory intraocular pressure elevation and optic nerve damage. Clinical outcomes are influenced by genetic polymorphisms, renal comorbidities, and the aqueous humor biomarker profile. Current anti-VEGF monotherapy is limited by its inability to control fibrosis and inflammation, highlighting the need for multifaceted therapeutic strategies incorporating anti-inflammatory and antifibrotic agents. Critical knowledge gaps remain in longitudinal human data and preclinical models. To improve the prognosis of this devastating disease, shifting toward systemic metabolic management and prospective multiomics-based risk stratification may represent future directions.