Plasma homocysteine and Endothelin-1 dysregulation: Insights into retinal endothelial dysfunction

Hyperhomocysteinemia (HHcy) is increasingly recognised as a contributor to vascular dysfunction; however, its role in retinal disease remains incompletely defined. This review provides a structured, mechanism-focused synthesis of experimental and clinical evidence examining the interaction between homocysteine, endothelin-1 (ET-1), and vascular endothelial growth factor (VEGF) signalling in the context of retinal endothelial dysfunction. HHcy promotes oxidative and endoplasmic reticulum stress, leading to nitric oxide depletion, endothelial nitric oxide synthase uncoupling, and upregulation of ET-1, thereby favouring vasoconstriction, inflammation, and vascular remodelling. In parallel, HHcy exerts complex, context-dependent effects on the VEGF pathway, including suppression of VEGF receptor signalling in endothelial cells and compensatory VEGF upregulation in non-endothelial cells. These convergent mechanisms may impair endothelial repair capacity and alter angiogenic responsiveness. A key limitation across mechanistic studies is the frequent use of supraphysiological homocysteine concentrations, which constrain direct clinical translation. Human studies suggest associations between elevated homocysteine and retinal vascular diseases, but causal relationships and therapeutic implications remain uncertain. Emerging clinical observations raise the possibility that HHcy may modulate vascular responses during anti-VEGF therapy, although current evidence is limited and exploratory. Overall, HHcy is best interpreted as a context-dependent modifier of endothelial vulnerability rather than a direct causal factor. Integrating metabolic, endothelial, and angiogenic pathways, this review proposes a translational framework to guide future research, emphasising physiologically relevant models, standardised biomarker assessment, and stratified clinical investigation in retinal vascular disease.