Multiscale Computational Modeling in Vascular Biology: From Molecular Mechanisms to Tissue-Level Structure and Function - Multiscale Computer Modeling in Biomechanics and Biomedical Engineering - page 207

of how blood vessels develop, maintain homeostasis, and respond to diseases
requires an approach that couples experiments with theoretical and computational
models and integrates processes across multiple length and time scales in a way
that ultimately captures the emergent behaviors of the complex system that we
know as a blood vessel.
This chapter will first provide an overview of vascular wall structure and many
of the well characterized molecular signals that underpin functional and dys-
functional cellular behaviors in vascular tissues. We will then briefly describe
some theoretical approaches, including continuum biomechanics, agent-based
modeling, and models of intracellular signaling, that have been applied at different
spatial scales to the study vascular function and adaptation. Examples from the
literature will be highlighted to depict how modeling has been fruitful in producing
new understanding at each level of spatial scale. We will then present our fun-
damental premise: that integration of processes across scales, as enabled by truly
integrated, multiscale computational models, can result in a new understanding of
emergent behaviors in vascular biology. This multiscale modeling approach, in
turn, is expected to reveal new categories of questions that can be posed—ques-
tions that embrace multi-dimensional cause-and-effect relationships. We have
developed the conceptual basis for such a multiscale model and begun integration
efforts for a combined tissue-level continuum mixture and multi-cell agent-based
model as well as for a combined agent-based and intracellular signaling model. We
will conclude with a summary of our goal to integrate models from continuum to
intracelluar scales and to highlight some of the opportunities and challenges posed
by integrative multiscale modeling of complex systems.
2 Background
2.1 Vascular Wall Structure
The microstructure of arteries and veins varies with species, age, disease, and
location along the vascular tree [ 30 ], yet the normal wall in maturity is charac-
terized by three primary layers—the intima, media, and adventitia (Fig. 1 ). The
intima, or inner layer, consists of a monolayer of endothelial cells (EC) and an
underlying basal lamina composed of mesh-like type IV collagen and adhesion
molecules such as laminin. In addition to being a smooth, nonthrombogenic
interface between the blood and contents of the wall, the endothelium is biolog-
ically active. In response to chemical and mechanical stimuli, ECs produce a host
of vasoactive molecules (which control vascular dilatation or constriction), growth
factors (which promote cell replication or synthesis of proteins), proteases (which
degrade proteins), and factors that regulate local immune responses and clotting
processes. The endothelium also modulates transport of substances into the wall
(e.g., white blood cells or lipids), and thereby plays important roles in diseases