Mechanical regulation of retinal vascular inflammation and degeneration in diabetic retinopathy

ABSTRACT Vascular inflammation is known to cause degeneration of retinal vessels in early diabetic retinopathy (DR). Past studies investigating these diabetes-induced vascular abnormalities have focused primarily on the role of molecular or biochemical cues. Here we show that retinal vascular inflammation and degeneration in DR are also mechanically regulated by retinal vascular stiffening that is caused by overexpression of collagen-crosslinking enzyme lysyl oxidase (LOX) in retinal vessels. Treatment of diabetic mice with LOX inhibitor BAPN prevented the increase in retinal vascular stiffness, vascular ICAM-1 overexpression, and leukostasis. Consistent with these anti-inflammatory effects, BAPN treatment of diabetic mice blocked the upregulation of proapoptotic caspase-3 in retinal vessels, which concomitantly reduced retinal vascular degeneration and the diabetes-induced loss of contrast sensitivity in these mice. Finally, we show that increasing substrate stiffness alone increases the adhesiveness and neutrophil elastase-induced death of cultured retinal endothelial cells. By uncovering a link between LOX-dependent vascular stiffening and the development of retinal vascular and functional defects in diabetes, these findings offer unique insights into DR pathogenesis that has important translational potential.