Diabetic Retinal Disease Revisited: Integrating Neurovascular Unit Dysfunction and Hemodynamics in Pathophysiology and Treatment.

Abstract

Studies have identified the involvement of microvascular injury, neurovascular unit (NVU) dysfunction, and retinal hemodynamic abnormalities in diabetic retinal diseases, including diabetic retinopathy and diabetic macular edema (DME). Although chronic hyperglycemia is the central driver of retinal damage, mounting evidence suggests that neuronal dysfunction, glial activation, impaired neurovascular coupling, and altered retinal circulation may occur before the development of clinically visible vascular lesions. These changes may reflect an early mismatch between neuronal metabolic demand and vascular supply, contributing to retinal ischemia and disease progression. In addition to vascular endothelial growth factor (VEGF)-mediated pathways, vasoactive and endothelial dysfunction-related factors, such as endothelin-1 and homocysteine, may further aggravate inflammation, oxidative stress, and circulatory impairment. Elevated retinal venous pressure, whose contribution to retinal hemodynamic dysregulation has gained increasing recognition, may also exacerbate ischemia and NVU injury. Advances in multimodal retinal imaging have improved the detection and characterization of these pathophysiological changes. Current management strategies entail integrated systemic and ocular approaches, including meticulous metabolic control and intravitreal anti-VEGF therapy. Future therapeutic strategies targeting inflammation, oxidative stress, non-VEGF pathways, and retinal hemodynamics may further improve the outcomes of diabetic retinal disease.