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At the macroscopic scale, hemodynamic forces impart shear stresses on the surface of the valve leaflets and cause deformation of the leaflet tissue. As discussed in this review, these macroscale forces are transduced to the microscale, where they influence the functions of the valvular endothelial cells that line the leaflet surface and the valvular interstitial cells that populate the valve extracellular matrix. For example, pathological changes in blood flow\u2013induced shear stress can cause dysfunction, impairing their homeostatic functions, and pathological stretching of valve tissue caused by elevated transvalvular pressure can activate valvular interstitial cells and latent paracrine signaling cytokines (eg, transforming growth factor-\u03b21) to promote maladaptive tissue remodeling. Collectively, these coordinated and complex interactions adversely impact bulk valve tissue properties, feeding back to further deteriorate valve function and propagate valve cell pathological responses. 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