Biomedical Engineering Reference
In-Depth Information
Other Factors Contributing to Angiogenesis
There are many other factors that play a role in the reestablishment of vascular
supply to bones during the healing process such as the fibroblastic growth factors
(FGF). Basic FGF is a strong fibroblast mitogen. It is also a chemotactic factor for
EC and is highly angiogenic. In contrast to VEGF, it is not specific for EC. FGF
receptors are expressed in EC and in smooth muscle cells, fibroblasts, myoblasts
and tumor cells [
6
].
Thrombin, found in fracture hematoma, is inherently angiogenic through its
action on protease activated receptors (PAR). Thrombin has been shown in vivo
and in vitro to act as a chemotactic factor for endothelial cells and to increase the
production of a
v
b
3
integrin on the surface of these cells. This integrin facilitates
migration, attachment and survival of endothelial cells [
121
].
The bone morphogenetic proteins (BMP), known for their ability to promote
mesenchymal stem cell differentiation that leads to bone formation, also promote
angiogenesis. Deckers et al. [
28
] found that BMP2, BMP4 and BMP6 were capable
of simulating murine derived osteoblasts to secrete VEGF in culture and stimulated
angiogenesis in fetal mice bone explants. The action of BMPs on osteoblasts
establishes a positive feedback loop where the BMP-induced VEGF release causes
vessel ingrowth, leading to the delivery of osteogenic precursor cells on which
BMPs will act to further increase VEGF concentrations at the fracture sire.
The extracellular matrix is critical for angiogenesis, and should be viewed as a
dynamic player in the process. In addition to providing a site for storage of growth
factors and pro-enzymes, for release and activation, its components serve as
binding sites and targets for endothelial and mesenchymal cell-derived integrins
and growth factors [
26
]. It also plays an important role in cell migration. Fibers
such as collagen, laminin and fibrillin are distributed through the ECM occupying
roughly 30% of the ECM. These fibers form bundles that serve as guiding
structures for migrating cells [
27
].
2.1.3 Mechanical Stimulation
The effect of mechanical stimulation in angiogenesis has been widely studied in
distraction osteogenesis [
17
,
23
,
32
,
54
,
55
,
92
,
126
] and bone healing [
51
,
119
]. In
a fixated fracture, the vascular network is rapidly reestablished and healing occurs
mainly by intramembranous ossification [
33
,
66
]. Conversely in an unstable
mechanical environment the spreading capillaries are disrupted and the hypoxic
environment promotes the differentiation of chondrocytes that stabilize the fracture
by cartilage formation. In distraction osteogenesis the effect of tension activates
biologic processes of the interfragmentary connective tissue. This includes the
prolongation of angiogenesis with increased tissue oxygenation and the increased
fibroblast proliferation with intensification of biosynthetic activity (Fig.
2
). In both
distraction osteogenesis and bone healing, lack of angiogenesis has been pointed
out as one of the main reasons for non-healing bone [
32
].
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