Abstract:Impairment of the retinal neurovascular unit (NVU) is a critical driver of blood-retinal barrier (BRB) dysfunction, which constitutes a major pathological basis for the onset and progression of diabetic retinopathy (DR). In the absence of timely therapeutic intervention, BRB disruption can contribute to diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR), ultimately leading to severe and irreversible visual impairment. The core pathomechanisms underlying BRB dysfunction during DR pathogenesis encompass the structural disorganization of intercellular junctional complexes, aberrant upregulation of vascular endothelial growth factor (VEGF), pathological accumulation of advanced glycation end products (AGEs), and sustained oxidative stress. Although the regulatory networks governing vascular permeability have been relatively well elucidated, the precise molecular circuitry that modulates BRB junctional proteins within the distinctive pathological microenvironment of DR remains incompletely understood. This review provides a systematic overview of the molecular architecture of the BRB, with a particular focus on the mechanisms by which aberrant remodeling of key junctional proteins—including tight junctions (TJs) and adherens junctions (AJs)—promotes microvascular leakage and macular edema throughout DR progression. A comprehensive understanding of these mechanistic cascades will inform the rational design of targeted interventions aimed at preserving BRB integrity and restoring the structural and functional homeostasis of the inner BRB, thereby mitigating retinal microvascular hyperpermeability and slowing DME progression.
