Multiscale Computational Modeling in Vascular Biology: From Molecular Mechanisms to Tissue-Level Structure and Function - Multiscale Computer Modeling in Biomechanics and Biomedical Engineering - page 212

Table 1 Some of the key
molecules produced and/or
expressed by vascular cells in
response to altered
hemodynamic loading,
disease, and injury

Vasoactive molecules Cytokines

Nitric oxide IL-1

Endothelin-1 IL-6

Angiotensin-II IL-8

Serotonin IL-10

Thromboxane SDF-1

Thrombin
Growth factors/receptors Proteinases

and modulators

PDGF-BB/PDGFR-alpha, beta MMP-2

VEGF/Flk-1, Flt-1, neuropilin MMP-9

TGF-b1/TGFBRI/II MMP-1

bFGF/FGF-R TIMP-1

EphrinB2/EphB4 TIMP-2

Cell-cell adhesion ECM proteins

P-selectin/PSGL-1 Type I collagen

E-selectin/PSGL-1 Type III collagen

CD-34/L-selectin Type IV collagen

VCAM-1/VLA-4 Elastin/Microfibrils

ICAM-1/LFA-1 & MAC-1 Laminin/Fibronectin

of molecules present in zebrafish, mice, and humans, and is a pivotal regulator of
growth and patterning in both the circulatory and nervous systems.
The key signaling pathways in the vascular tree can be broadly lumped into
functional categories based on their ability to mediate vascular tone (vasoactive
molecules), activate cells (cytokines), induce growth (growth factors), form and
impact the extracellular milieu (ECM molecules and proteinases), and orchestrate
cell adhesion (Table 1 ). While a comprehensive review of all of these key sig-
naling pathways is beyond the scope of this chapter, we highlight some of the most
widely studied molecules that play a diverse set of context-specific roles in the
vasculature. We thus focus on a small sub-set of signaling pathways that are
particularly important in mediating vascular responses to physiological and
pathological alterations and those that are most relevant in our proposed multiscale
model of hypertension, which is discussed in subsequent sections.
NO is one of the most widely studied signaling molecules in the vasculature. It
exerts its effects at both systemic and cellular levels throughout the microcircu-
lation and in larger vessels throughout the body. This highly diffusible and short-
lived free radical gas is synthesized via nitric oxide synthases [ 35 ], a family of
enzymes that convert L -arginine to NO (for review of this process in ECs see [ 54 ]).
Impaired NO activity, due to decreased synthesis or increased degradation, is a
hallmark of endothelial dysfunction and has been observed in a host of conditions
and diseases ranging from aging to atherosclerosis, hypertension, and diabetes
[ 47 ]. NO is a potent vasodilator [ 12 ] and thus regulates vascular SMC tone. Both
exogenous NO [ 48 , 72 ] and over-expression of endothelial nitric oxide synthase