Biomedical Engineering Reference
In-Depth Information
incorporating events across these three levels, thus providing a means to predict
phenomena that can only emerge from a system of integrated interactions.
1 Introduction: Vascular Biology as a Complex System
Vascular development, adaptations to altered hemodynamics, the progression of
disease, and responses to injury or clinical treatment—in each of these cases, one
can identify tissue-level changes in geometry, structure, function, and properties
that result from altered cellular phenotypes, which in turn depend on changes in
intracellular signaling pathways. Indeed, our knowledge of the complex web of
signals that underpin vascular function, homeostasis, growth, and remodeling at
different levels of biological scale is growing exponentially as more sophisticated
experimental models, techniques for analysis, and tools for integrating data
become available. Recent technological developments in molecular biology and
bioinformatics have thus made high-throughput analyses commonplace and ''-
omics'' data widely accessible. The empirical tools we can use to manipulate and
measure vascular structure, function, and adaptation in vivo—ranging from
inducible genetic manipulations in mice to non-invasive intravital microscopy with
single-cell resolution—are more flexible and precise than ever before. Parallel
advances in systems biology, agent based modeling, continuum biomechanics, and
computational methods have enabled significantly increased understanding of
vascular biology at molecular, cellular, and tissue levels.
Despite all of these advances, critical questions in vascular mechanobiology—
that is, many of the big questions that impact the care of thousands of patients each
year—remain unanswered. For example, how do medial vascular smooth muscle
cells (SMC) transduce mechanical stimuli in a way that impacts their production
and secretion of proteases that degrade the extracellular matrix (ECM)? How, in
turn, does degradation of ECM liberate growth factors that impact the proliferation
of adventitial fibroblasts? What mechanical stimuli induce endothelial-to-mesen-
chymal transition and how does this perturb homeostasis? Similarly, many ques-
tions remain regarding interactions between wall mechanics and pharmacological
treatments. What impact, for example, would a calcium channel blocker have on
the stiffness of an arterial wall in the presence of a stiff atherosclerotic plaque that
occludes 50 % of the lumen? While it is no small task to study such questions in
isolation, the prospect of conceptualizing how these phenomena interact in space
and time to create an emergent response is even more daunting. Indeed, the dif-
ficulty in answering these questions arises not from our ignorance of the individual
components that are relevant in this complex system, but rather from the way in
which they integrate to produce emergent outcomes. Even when we understand
singular cause-and-effect relationships between two components, we face the
challenge of integrating sets of relationships across different spatiotemporal scales
in these complex systems. We submit that achieving a more holistic understanding
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