<b>Mechanical regulation of retinal vascular inflammation and degeneration</b><b>in diabetes</b>

ABSTRACTVascular inflammation is known to cause degeneration of retinal capillaries in early diabetic retinopathy (DR), a major microvascular complication of diabetes. Past studies investigating these diabetes-induced retinal vascular abnormalities have focused primarily on the role of molecular or biochemical cues. Here we show that retinal vascular inflammation and degeneration in diabetes are also mechanically regulated by the increase in retinal vascular stiffness caused by overexpression of collagen-crosslinking enzyme lysyl oxidase (LOX). Treatment of diabetic mice with LOX inhibitor β-Aminopropionitrile (BAPN) prevented the increase in retinal capillary stiffness, vascular ICAM-1 overexpression, and leukostasis. Consistent with theseanti-inflammatory effects, BAPN treatment of diabetic mice blocked the upregulation of proapoptotic caspase-3 in retinal vessels, which concomitantly reduced retinal capillary degeneration, pericyte ghost formation, and the diabetes-induced loss of contrast sensitivity in these mice. Finally, our in vitro studies indicate that retinal capillary stiffening is sufficient to increase the adhesiveness and neutrophil elastase-induced death of retinal endothelial cells.By uncovering a link between LOX-dependent capillary stiffening and the development of retinal vascular and functional defects in diabetes, these findings offer a new insight into DR pathogenesis that has important translational potential.ARTICLE HIGHLIGHTS· The objective of this study was to determine whether retinal vascular inflammation and degeneration associated with early DR are mechanically regulated by the increased stiffness of retinal capillaries· We provide first direct evidence of retinal capillary stiffening in diabetes that is dependent on LOX, promotes retinal vascular inflammation, and causes capillary degeneration by increasing retinal endothelial susceptibility to neutrophil elastase· We also show that pharmacological inhibition of LOX prevents the diabetes-induced loss of contrast sensitivity These findings implicate LOX and capillary stiffening as new anti-inflammatory targets for the treatment of retinal vascular and functional defects associated with early DR