Arteries exist in a dynamic environment, necessitating constant adaptation by vascular smooth muscle cells (VSMCs), in order to maintain mechanical homeostasis. In a healthy artery, maintenance of vessel tension is primarily achieved by contraction and relaxation of VSMCs, and loss of contractility is indicative of VSMC dysfunction, which may play an important role in pathogenesis of atherosclerotic plaque formation and restenosis. The mechanical environment can be significantly perturbed by plaque development or stent implantation, either by softening of the tissue, due to lipid pools in atherosclerosis, or stiffening due to calcified regions of the plaque, or an implanted stent. Recent results have found that the mechanics of a cell's surroundings play a significant role in its functional behavior, suggesting that non-homeostatic tissue mechanics, due to plaques or stents, could also affect contractile function. We hypothesize that the mechanics of the surrounding tissue directly affects vascular smooth muscle cells'contractile functionality. With current techniques, it is difficult to assess the effects of tissue stiffness on VSMC function because existing in vitro systems in which mechanics are independently controllable are all limited to narrow ranges of substrate stiffness over which they can be used to measure cell or tissue stress generation. So, to test this hypothesis we will need to develop a new method for measuring tissue stress that can be employed with a wide range of substrate mechanics. We have previously developed a method called vascular muscular thin films (vMTFs), where we micropatterned cells into highly organized tissues on a thin rubber beam, and the cell stress was determined by measuring the curvature of the beam. We will adapt this method to include a variable modulus substrate, allowing us to measuring functional contractility of VSMCs mimicking a wide range of mechanical environments, such as soft lipid pools and stiff stents. We will then correlate this contractility with VSMC phenotype marker expression to determine how phenotype switching, which has been implicated in a number of VSMC dysfunctions, plays a role in VSMC substrate-modulated mechano-adaptation. Completion of this work will provide a sharper picture of the functional implications of the evolving mechanical environment of VSMCs in arterial pathologies.
In a healthy artery, vascular smooth muscle cells maintain vessel tension by contracting and relaxing. Loss of this contractility may play an important role in atherosclerosis development, and complications following stenting of atherosclerotic arteries. In this project, we will test whether changes in vessel mechanics brought on by atherosclerosis or stenting directly affect the ability of smooth muscle cells to function effectively.
|Ray, Arja; Lee, Oscar; Win, Zaw et al. (2017) Anisotropic forces from spatially constrained focal adhesions mediate contact guidance directed cell migration. Nat Commun 8:14923|
|Steucke, Kerianne E; Tracy, Paige V; Hald, Eric S et al. (2015) Vascular smooth muscle cell functional contractility depends on extracellular mechanical properties. J Biomech 48:3044-51|