Mechanobiological Modelling of Angiogenesis: Impact on Tissue Engineering and Bone Regeneration - Computational Modeling in Tissue Engineering - page 370

2.1.1 The Role of Hypoxia
It has been proved that hypoxia is the major initiator of both fetal and adult
angiogenesis [ 74 ] (Fig. 1 ). In fact, there is a close link between hypoxia and the
upregulation of proangiogenic factors, such as VEGF [ 110 ]. The transcription
factor responsible is named hypoxia inducible factor-1 (HIF-1) which activates
genes involved in anaerobic metabolism, angiogenesis and erythopoiesis. How-
ever, severe hypoxia, as is often noted in infected open wounds, cannot sustain the
growth of functional blood vessels [ 52 , 87 , 106 ].
2.1.2 Chemical Stimulation
Chemical stimulation of angiogenesis is performed by various angiogenic proteins,
including several angiogenic growth factors.
Vascular Endothelial Growth Factors
It is the most studied growth factor and the major regulator of neovascularization
under physiological and pathological conditions [ 8 ]. It was initially defined by its
ability to induce vascular leak and permeability, and thus promote EC migration
and proliferation [ 73 , 125 ]. It is produced by numerous cell types, including
endothelial cells, macrophages, fibroblasts, smooth muscle cells, osteoblasts and
hypertrophic chondrocytes [ 9 , 28 , 63 ].
Numerous studies have shown that the expression of VEGF is tightly associated
with blood vessel invasion of hyaline cartilage, growth plate morphogenesis,
cartilage remodelling and bone repair [ 42 , 95 , 119 , 128 ]. VEGF is expressed in
much the same temporal and spatial pattern in the fracture callus as that occurs
during long bone development [ 33 , 46 ]. The human fracture hematoma, present
after injury but not during development, has potent angiogenic activity that
appears to be predominantly due to VEGF [ 117 , 118 ].
Inhibition of VEGF activity disrupts repair of femoral fractures and cortical
bone defects in mice [ 119 ] and decreases blood flow and leads to non-unions in
rabbit radial fractures [ 24 ]. These findings support the idea that VEGF production
is the major mechanism by which angiogenesis and osteogenesis are tightly
coupled during bone repair [ 95 , 119 ]. Given the importance of VEGF in normal
bone repair, treatment with exogenous VEGF is expected to promote angiogenesis.
In fact VEGF treatment increases bone blood flow in rabbit radial fractures [ 24 ]
and in rabbit tibiae during distraction osteogenesis [ 30 ].
In addition to contributing to vasculogenesis and angiogenesis during embry-
onic development and bone regeneration processes, VEGF is an essential factor in
angiogenesis-dependent diseases [ 16 , 34 ]. For instance, VEGF is a key angiogenic
factor in tumors, which express it at high levels. Overexpression of VEGF can also
cause vascular disease in the retina of the eye and other parts of the body. Drugs
such as bevacizumab can inhibit VEGF and control or slow those diseases [ 122 ].