Basement membrane stiffening promotes retinal endothelial activation associated with diabetes

摘要: Endothelial activation is a hallmark of the high-glucose (HG)-induced retinal inflammation associated with diabetic retinopathy (DR). However, precisely how HG induces endothelial not fully understood. We hypothesized that HG-induced up-regulation lysyl oxidase (LOX), collagen-cross-linking enzyme, in capillary cells (ECs) enhances subendothelial basement membrane (BM) stiffness, which, turn, promotes EC activation. Diabetic C57BL/6 mice exhibiting 70 and 50% increase intercellular adhesion molecule (ICAM)-1 expression leukocyte accumulation, respectively, demonstrated 2-fold levels BM collagen IV LOX, key determinants stiffness. Using atomic force microscopy, we confirmed significantly LOX-dependent matrix stiffness vitro, which correlated an ∼2.5-fold ICAM-1 expression, 4-fold greater monocyte-EC adhesion, ∼2-fold alteration NO (decrease) NF-κB (increase). Inhibition stiffening alone suppressed Finally, using synthetic matrices tunable necessary sufficient to promote These findings implicate as critical determinant provide rationale for examining underlying mechanotransduction pathways therapeutic targets retinopathy.