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Mechanical regulation of retinal vascular inflammation and degenerationin diabetes

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posted on 2023-11-21, 00:10 authored by Sathishkumar Chandrakumar, Irene Santiago Tierno, Mahesh Agarwal, Emma M. Lessieur, Yunpeng Du, Jie Tang, Jianying Kiser, Xiao Yang, Anthony Rodriguez, Timothy S. Kern, Kaustabh Ghosh

ABSTRACT

Vascular 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 these
anti-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

Funding

U.S. Department of Health and Human Services > National Institutes of Health > National Eye Institute EY022938-S1 to E.M.L P30EY034070-01 NEI core grant to C.T.V.R at UCI R01EY022938 to T.S.K R01EY028242 to K.G R01EY033002 to T.S.K R24EY024864 to T.S.K

Unrestricted Grants from Research to Prevent Blindness, Inc. x Dept. of Ophthal., UCLA & Gavin Herbert Eye Inst.,

Ursula Mandel Fellowship and UCLA Graduate Council Diversity Fellowship x

W.M. Keck Foundation x The Stephen Ryan Initiative for Macular Research

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