Biomedical Engineering Reference
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(eNOS) promote angiogenesis [
56
]. Interestingly, NO and eNOS also upregulate
and are synergistic with pro-angiogenic growth factors, such as VEGF and An-
giopoietin-1 [
10
]. This relationship supports an intriguing mechanistic linkage
between hemodynamic alterations due to vasodilation and growth factor mediated
angiogenesis. NO also plays a role in mediating microvascular permeability (for
review see [
22
]) and inflammation by inhibiting platelet adhesion, aggregation,
and leukocyte adhesion [
24
].
NO production via eNOS has long been associated with the mechanical shear
stress experienced by the vascular endothelium of large vessels (e.g., during
sustained changes in blood flow) and is critical for blood flow-dependent adaptive
remodeling of the media [
50
], yet a direct molecular linkage between NO and
SMC remodeling (proliferation and apoptosis) was only recently discovered by Yu
et al. [
69
]. They demonstrated that abnormal flow-dependent remodeling in eNOS
knockout mice is associated with activation of the PDGF signaling pathway and
downstream inhibition of apoptosis. Moreover, they showed that NO negatively
regulates PDGF-induced cell proliferation in vascular SMCs. Hence, this signaling
module represents yet another example of the mechanistic linkages between
mechanical forces experienced by blood vessels, diffusible signals and morpho-
gens secreted by cells, and defined cellular behaviors that have important conse-
quences on long-term vascular tissue structure and function.
As mentioned above, PDGF is a family of growth factors synthesized and
secreted by vascular ECs and SMCs in homodimeric (e.g., PDGF-AA and PDGF-
BB) and heterodimeric (e.g., PDGF-AB) forms [
20
]. PDGF homodimers and
heterodimers bind to dimeric tyrosine kinase receptors, PDGFR-alpha and
PDGFR-beta, with different affinities. PDGF is a potent mitogen for SMCs and
fibroblasts, stimulating proliferation, migration, and preventing apoptosis [
41
]
(Fig.
2
). Dysfunction of the PDGF signaling pathway has been implicated in a
number of diseases, including pulmonary hypertension [
51
], cancer [
38
], renal
disease [
41
], and diabetic retinopathy [
66
]. There is extensive evidence that
implicates PDGF in inhibiting SMC differentiation, and the extensive intracellular
machinery (e.g., gene promoters and repressors) that enact its ability to shift SMC
phenotypes from differentiated to synthetic/proliferative are well described [
67
];
for a review, see Ref. [
36
]. How the phenotypic states of a collection of SMCs
within the medial wall, in turn, impact the mechanical stiffness of that tissue,
which may further be influenced by regional NO levels, is less well understood and
requires the type of multiscale modeling that we will focus on in subsequent
sections of this chapter.
Thus far in this section, we have highlighted how small molecule signals (e.g.,
NO) and growth factors (e.g., PDGF) impact vascular adaptation, but we would be
remiss to leave out the impact that ECM and its modifiers have on vascular growth
and remodeling. While various extracellular proteins and glycoproteins (e.g.,
elastin, fibrillins, and fibulins: see Ref. [
62
]) provide a substrate for vascular cell
assembly and stability, proteolytic enzymes such as the MMPs critically impact
vessel homeostasis and adaptation by degrading the ECM (Fig.
2
) and by medi-
ating intercellular signaling (for review see Ref. [
46
]). The MMP family includes
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