Cell signaling model for arterial mechanobiology

Author summary Biological soft tissues are characterized by continuous production and removal of material, which endows them with a remarkable ability to adapt to changes in their biochemical and biomechanical environments. For arteries, mechanical stimuli result primarily from changes in blood pressure or flow, and biochemical changes are induced by multiple factors, including pharmacological intervention. In order to understand how arterial properties are maintained in health, or how they adapt or fail to adapt in disease, we must understand better how these diverse stimuli affect material turnover. Extracellular matrix is tightly regulated by mechano-sensing and mechano-regulation, and therefore cell signaling, thus we present a computational model of relevant signaling pathways within the vascular wall, with the aim of predicting changes in wall composition and function in response to three main inputs: pressure-induced wall stress, flow-induced wall shear stress, and exogenous angiotensin II. We obtain qualitative agreement with a range of experimental studies from the literature, and provide illustrative examples demonstrating how such models can be used to further our understanding of arterial remodeling. Arterial growth and remodeling at the tissue level is driven by mechanobiological processes at cellular and sub-cellular levels. Although it is widely accepted that cells seek to promote tissue homeostasis in response to biochemical and biomechanical cues-such as increased wall stress in hypertension-the ways by which these cues translate into tissue maintenance, adaptation, or maladaptation are far from understood. In this paper, we present a logic-based computational model for cell signaling within the arterial wall, aiming to predict changes in extracellular matrix turnover and cell phenotype in response to pressure-induced wall stress, flow-induced wall shear stress, and exogenous sources of angiotensin II, with particular interest in mouse models of hypertension. We simulate a number of experiments from the literature at both the cell and tissue level, involving single or combined inputs, and achieve high qualitative agreement in most cases. Additionally, we demonstrate the utility of this modeling approach for simulating alterations (in this case knockdowns) of individual nodes within the signaling network. Continued modeling of cellular signaling will enable improved mechanistic understanding of arterial growth and remodeling in health and disease, and will be crucial when considering potential pharmacological interventions.