Cells within mechanically dynamic tissues like arteries are exposed to ever-changing forces and deformations. In some pathologies, like aneurysms, complex loads may alter how cells transduce forces, driving maladaptive growth and remodeling. Here, we aimed to determine the dynamic mechanical properties of vascular smooth muscle cells (VSMCs) under biaxial load. Using cellular micro-biaxial stretching microscopy, we measured the large-strain anisotropic stress-strain hysteresis of VSMCs and found that hysteresis is strongly dependent on load orientation and actin organization. Most notably, under some cyclic loads, we found that VSMCs with elongated in-vivo-like architectures display a hysteresis loop that is reverse to what is traditionally measured in polymers, with unloading stresses greater than loading stresses. This reverse hysteresis could not be replicated using a quasilinear viscoelasticity model, but we developed a Hill-type active fiber model that can describe the experimentally observed hysteresis. These results suggest that cells in highly organized tissues, like arteries, can have strongly anisotropic responses to complex loads, which could have important implications in understanding pathological mechanotransduction.
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