Empirical Determination of Vascular Smooth Muscle Cell Mechano-Adaptation

Abstract

Patient-specific vascular modeling seeks to provide physicians with predictive data that will enable them to make better treatment decisions and improve patient outcomes. To achieve this, these models must incorporate the mechanical response of the arterial components including the key mechanically active component - vascular smooth muscle cells (VSMCs). However, current models fail to incorporate the dynamic mechanically-induced VSMC growth and remodeling, or mechano-adaptation, behavior. Therefore, the focus of this work is to mathematically characterize VSMC mechano-adaptation using experimentally determined VSMC functional responses to perturbations in the surrounding mechanical environment. To test this hypothesis, we developed three experimental techniques and proposed two VSMC mechano-adaptation laws. First, we asked if vascular disease relevant changes in extracellular matrix mechanical properties would affect tissue-scale VSMC functional contractility. We adapted the muscular thin film assay to control the underlying substrate modulus and found that with increasing substrate modulus there is increasing VSMC contractility. Second, we asked if a simple growth law could capture single cell VSMC mechano-adaptation. To derive a VSMC mechano-adaptation law from experimental data, we engineered a chronic strain traction force microscopy method, which enabled us to apply a chronic step change in strain to micropatterned single VSMCs and measured their internal stress generation over time. We found that single VSMCs have a preferred homeostatic stress-state, referred to as target stress, that they return to if perturbed. This dynamic growth and remodeling response was described by a set of simple growth laws we termed a VSMC mechano-adaptation law. Finally, we elucidated the relationship between single VSMC mechano-adaptation and substrate modulus. To determine this law from experimental findings, we adapted the previous chronic strain traction force microscopy assay, such that the substrate modulus could be altered. We then tracked the temporal stress evolution of single VSMCs on three different substrate moduli and used those data to develop a substrate dependent VSMC mechano-adaptation law.