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In a healthy blood vessel, endothelial cells dynamically integrate biomechanical and biochemical signals from the flowing blood at their apical surface and the basement membrane at their basolateral surface. In disease, changes in the biochemical environment may disturb endothelial cell response to mechanical forces, and the mechanical environment may affect biochemical kinetics. In this talk, I will present our research demonstrating that altered blood glucose, such as that experienced by people with diabetes, disturbs endothelial cell mechanotransduction in response to shear stress and cyclic strain. I will also describe how substrate stiffness impacts endothelial cell response to inflammatory stimuli and collective migration. Our research highlights how interrelated changes in glucose and flow may accelerate atherosclerotic plaque development and disordered angiogenesis in people with diabetes.