Biomedical Engineering Reference
In-Depth Information
may also depend on the physical properties of the ECM. In this chapter, we will
discuss the important factors that govern ECM remodeling during angiogenesis,
focusing on the links between proteinases, stromal cells, and matrix physical
properties. The impact of these possible links on therapeutic and pathologic
angiogenesis will also be discussed.
1 Introduction
During angiogenesis, the ECM dynamically evolves, changing and adapting to
cellular processes that are taking place within its structure. As ECs differentiate
into tubular structures containing lumens and associated pericytes, significant
matrix remodeling occurs. Proteinases carve out areas to allow for invasion of the
nascent tubular structures into the surrounding stroma, creating new vasculature in
response to hypoxia. A new basement membrane is laid down, and supporting
interstitial matrix is layered beneath the newly formed structures. This chapter will
discuss angiogenesis as it relates to the surrounding ECM, the various proteinases
that are able to modulate key steps of this process, and finally, the link between
ECM mechanical properties and cellular remodeling during angiogenesis.
Vasculogenesis and angiogenesis are two distinctly different processes by
which blood vessels form (Fig.
1
). In embryonic development, angioblastic cells
assemble into a primary capillary plexus to create nascent vasculature de novo via
vasculogenesis. By contrast, angiogenesis refers to the formation of capillaries via
branching from existing vasculature after initial embryonic development. This
requires a complex series of events starting with basement membrane degradation
of the existing vasculature, followed by endothelial cell activation, migration, and
proliferation, organization into immature vessel sprouts with leading tip cells,
maturation and vessel stabilization via mural cell association, and finally, base-
ment membrane deposition and pruning of the new vessels in response to the
physiologic demands of the tissue [
1
]. Each step in this process requires interaction
between cells and their surrounding ECM.
A balance between pro- and anti-angiogenic proteins, known as the 'angiogenic
switch', is crucial to the control of angiogenesis, with soluble factors and insoluble
factors actin regulating this switch. When the scale is tipped in favor of molecules
that inhibit angiogenesis, the switch is 'off' until the levels of activating
(pro-angiogenic) molecules are increased and able to overcome the inhibiting
molecules. In healthy adults, the switch is typically maintained in the 'off' posi-
tion, unless a pathological state which requires the formation of new vasculature
occurs, such as cancer, wound healing, or ischemic disease. (In cancer, tumor
growth beyond a threshold is achieved in part by recruiting host vasculature;
however, because a detailed discussion of tumor angiogenesis is beyond the scope
of this chapter, readers should refer to other reviews on the topic instead [
2
].)
Many signals can tip the switch in favor of angiogenesis, such as hypoxia, low
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