Characterization of the Dynamic Mechanical Properties of Single Cardiovascular Cells

Abstract

Cardiovascular tissues are exposed to complex strains during the cardiac cycle in vivo. Strains can change as a result of disease and surgical interventions necessitating tissues to mechanoadapt to maintain function. Biomechanical models provide insight into tissue behavior and disease progression that can be incorporated into clinically relevant models for guiding treatment to improve patient outcomes. Frameworks for modeling tissue mechanical properties, such as the constrained mixture model, require mechanical descriptions of each individual component of the tissue. For models of cardiovascular tissues, the mechanical behavior of the force generating cells, including vascular smooth muscle cells (VSMCs) in arteries and cardiac myocytes in the heart, must be considered. Cellular microbiaxial stretching (CμBS) is used to measure and characterize the anisotropic mechanics of cells with in vivo like geometries. Here, CμBS is used to investigate the dynamic mechanical properties of single cardiovascular cells to better understand changes in mechanical function and cytoskeletal structure in response to large biaxial strains. First, the contributions of VSMCs to the large-strain nonlinearity of whole vessel mechanics was investigated using CμBS. The mechanical properties of VSMCs with native-like architectures are highly anisotropic, due to their highly aligned actomyosin cytoskeletons, but inhibition of actomyosin contraction results in nearly isotropic material properties. Additionally, VSMCs have a surprisingly linear stress-strain relationship even at large deformations, and a Holzapfel-Gasser-Ogden type strain energy density function is used to describe individual VSMCs mechanical properties. To further understand the mechanical behavior of VSMCs to complex loading conditions, cell stress in response to both extension and compression as well as immediate temporal changes in stress in response to cyclically applied deformations were measured. VSMCs display clear hysteresis under incremental extension and compression and demonstrate cycle-dependent stress-relaxation after cyclic step change extension and compression. A Hill-type active fiber model reproduces all observed hysteresis and cycle-dependent stress-relaxation, suggesting that the temporal stress–strain behavior of the cell is regulated by actomyosin contraction and relaxation, rather than passive viscoelasticity. Finally, the sarcomere length-tension relationship in single neonatal cardiac myocytes was investigated using CμBS. Cardiac myocytes have a highly organized structure. Using CμBS, the length between sarcomeres was changed as a function of applied stretch. When stretching cells such that the length between sarcomeres changes, the force generated by the cells changes consistent with previous understanding of the length-tension curve. Stretching cells perpendicular to sarcomere alignment holds the length between sarcomeres relatively constant, but the active force of contraction changes with stretch, decreasing as the cell was extended and compressed. A relatively simple active contraction based model, dependent on lattice and sarcomere spacing, robustly recapitulates the experimentally observed behavior. These results indicate that the active force of contraction of cardiac myocytes is dependent on both lattice spacing and length between sarcomeres. Altogether, this work aims to elucidate the nonlinear mechanical properties of cardiovascular cells and aid in creating constitutive models of cardiovascular mechanics. This has important implications for modeling in mechanobiology as VSMCs and cardiac myocytes are mechanosensitive and actively remodel to maintain function.