Glycated Collagen Impairs Endothelial Cell Response to Cyclic Stretch

People with diabetes suffer from accelerated, diffuse atherosclerosis. Endothelial cells are dysfunctional in high glucose and on glycated collagen, but their response to mechanical stimuli in a high glucose environment has not been examined. The aim of this study was to determine the effect of glycated collagen on aortic endothelial cell response to strain. Porcine aortic endothelial cells seeded on either native or glycated collagen coated elastic substrates were exposed to 10% cyclic strain. While cells on native collagen aligned and formed actin stress fibers perpendicular to the stretch direction after 6 h, cells on glycated collagen did not align even after 12 h of cyclic strain. Impaired actin alignment could be related to diminished focal adhesion kinase phosphorylation in cells on glycated collagen. We further show that loss of mechanotransduction affects endothelial cell barrier function. Cells on glycated collagen substrates demonstrated a threefold increase in permeability with strain, whereas cell permeability on native collagen was unchanged. Increased permeability could be related to altered cell-cell junction morphology, as evidenced by beta-catenin immunofluorescence. We hypothesize that impaired endothelial cell mechanotransduction on glycated collagen is due to altered integrin interactions. These data suggest that endothelial cells exposed to diabetic hyperglycemia are unable to adapt to the mechanical environment and thereby continue to express a pro-atherosclerotic phenotype.