title: On the Functional Role of Valve Interstitial Cell Stress Fibers: A Continuum Modeling Approach.
abstract: The function of the heart valve interstitial cells (VICs) is intimately connected to heart valve tissue remodeling and repair, as well as the onset and progression of valvular pathological processes. There is yet only very limited knowledge and extant models for the complex three-dimensional VIC internal stress-bearing structures, the associated cell-level biomechanical behaviors, and how they change under varying activation levels. Importantly, VICs are known to exist and function within the highly dynamic valve tissue environment, including very high physiological loading rates. Yet we have no knowledge on how these factors affect VIC function. To this end, we extended our previous VIC computational continuum mechanics model (Sakamoto, et al., 2016, "On Intrinsic Stress Fiber Contractile Forces in Semilunar Heart Valve Interstitial Cells Using a Continuum Mixture Model," J. Mech. Behav. Biomed. Mater., 54(244-258)). to incorporate realistic stress-fiber geometries, force-length relations (Hill model for active contraction), explicit α-smooth muscle actin (α-SMA) and F-actin expression levels, and strain rate. Novel micro-indentation measurements were then performed using cytochalasin D (CytoD), variable KCl molar concentrations, both alone and with transforming growth factor β1 (TGF-β1) (which emulates certain valvular pathological processes) to explore how α-SMA and F-actin expression levels influenced stress fiber responses under quasi-static and physiological loading rates. Simulation results indicated that both F-actin and α-SMA contributed substantially to stress fiber force generation, with the highest activation state (90 mM KCL + TGF-β1) inducing the largest α-SMA levels and associated force generation. Validation was performed by comparisons to traction force microscopy studies, which showed very good agreement. Interestingly, only in the highest activation state was strain rate sensitivity observed, which was captured successfully in the simulations. These unique findings demonstrated that only VICs with high levels of αSMA expression exhibited significant viscoelastic effects. Implications of this study include greater insight into the functional role of α-SMA and F-actin in VIC stress fiber function, and the potential for strain rate-dependent effects in pathological states where high levels of α-SMA occur, which appear to be unique to the valvular cellular in vivo microenvironment.
authors.affiliation: Center for Cardiovascular Simulation, Institute for Computational Engineering and Sciences, Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sakamoto
authors.affiliation: Center for Cardiovascular Simulation, Institute for Computational Engineering and Sciences, Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Buchanan
authors.affiliation: Departments of Orthopaedic Surgery, Duke University Medical Center, Durham, NC 27710;Departments of Biomedical Engineering, Duke University Medical Center, Durham, NC 27710.
authors.forename: Johannah
authors.initials: J
authors.lastname: Sanchez-Adams
authors.affiliation: Departments of Orthopaedic Surgery, Washington University, St. Louis, MO 63110;Departments of Biomedical Engineering, Washington University, St. Louis, MO 63110;Departments of Developmental Biology, Washington University, St. Louis, MO 63110.
authors.forename: Farshid
authors.initials: F
authors.lastname: Guilak
authors.affiliation: W. A. "Tex" Moncrief, Jr. Simulation-Based Engineering Science Chair I Center for Cardiovascular Simulation, Institute for Computational Engineering and Sciences, Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712 e-mail: msacks@ices.utexas.edu.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Sacks
mesh_terms: D000818:Animals; D003198:Computer Simulation; D006351:Heart Valves / Q000166:cytology* / Q000502:physiology*; D006801:Humans; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D008955:Models, Cardiovascular; D020409:Molecular Motor Proteins / Q000502:physiology; D009200:Myocardial Contraction / Q000502:physiology*; D022502:Stress Fibers / Q000502:physiology*; D013314:Stress, Mechanical
chemical_list: D020409:Molecular Motor Proteins