Multi-scale modeling of microvascular reactivity

Regulation of vascular tone is a complex process that remains poorly understood. Here we present our recent efforts for the development of physiologically realistic model of an arteriole for the analysis of vasoreactivity in health and in disease. Our goal is to describe function at a macro scale level by integrating mechanisms at the subcellular/molecular level. The behavior of a cell component (i.e. current-voltage relationship of an ion channel) or a signaling pathway is described through mathematical formulations. Modeling integrates intracellular and cell membrane components into whole-cell models of calcium and membrane potential dynamics. Cellular models are coupled (i.e. through diffusion of ions and second messengers) and multi-cellular models of the vascular wall are generated, capable of investigating intercellular communication and signaling. The detailed calcium dynamics and electrophysiology models are combined with a biomechanics model to describe function at the vessel level (i.e. diameter responses to agonist or hemodynamic stimulation). At each scale, continuum models can account for spatial heterogeneity in calcium signaling and contractility. High-throughput gene expression data inform the model of changes in activity of a component (i.e. conductance of an ion channel, concentration of a protein, density of pumps and receptors) in hypertension, to appropriately modify model parameters. Thus, the outlined approach can be used to investigate cellular mechanisms underlying altered peripheral vascular resistance in hypertension.