CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 9, October 2012
AFRICA
509
CAM (ICAM) and vascular CAM (VCAM). Where ICAM
binds to integrins present on all leukocytes, VCAM binds to
the VLA-4 ligand which is present on lymphocytes, monocytes
and eosinophils. Both have been implicated in atherosclerotic
lesions.
37
Activated vascular endothelial cells express elevated levels
of CAMs at their surface in the initial phases of atherosclerostic
plaque formation. Even though the role of arterial pressure on
atherosclerotic plaque development is not fully known, reports
have shown high concentrations of circulating ICAM, VCAM,
E-selectin and MCP-1 in hypertensive patients.
38,39
Where E- and
P-selectin are thought to play a role in atherogenesis, E-selectin
participates in the binding of neutrophils and monocytes to
endothelial surfaces.
Following vascular injury, CAMs such as ICAM, and
E-, L- and P-selectin are responsible for the leukocyte and
specifically neurophil accumulation on the injured vessel wall,
and various experimental studies have shown their potential
role in the initiation and/or development of NIH in both animals
and humans.
40-42
Also, Shimazawa
et al.
(2005)
showed that the
interaction between neutrophil L- and P-selectin with sulfatides,
which are ligands for L- and P-selectin, potentially contribute to
the development of NIH following vascular injury.
42
Nuclear factor kappa B (NF-
κ
B)
NF-
κ
B is a nuclear transcription factor which regulates at
least 200 genes involved in cellular proliferation and immune
and inflammatory responses. As atherosclerosis is a chronic
inflammatory disease, it is not surprising that NF-
κ
B plays
an essential role in the development of atherosclerosis. Riou
et al
. (2007)
showed a direct link between hypertension and
the development of atherosclerosis through the induction of
NF-
κ
B.
43
Rather than affecting SMC proliferation, it has been
suggested that NF-
κ
B is involved in apoptotic and inflammatory
signalling of vascular SMCs.
44
Furthermore, NF-
κ
B plays a
crucial role in controlling vascular inflammation and NIH.
45
A recent study by Bu
et al
. (2010)
suggested that activation of
NF-
κ
B in neo-intimal SMCs following vascular injury induces
the expression of a catalytic telomerase reverse transcriptase
(
TERT). This is one of two core components of the enzyme
telomerase, which is responsible for adding DNA sequence
repeats to the 3
′
ends of DNA strands and is essential to the
replicative longevity of vascular cells.
45
In addition, studies have shown that neutrophil accumulation
after vascular endothelial injury contributes not only to the
development but also to the initiation of NIH.
46
Moreover, the
pre-operative neutrophil NF-
κ
B status has been suggested as a
marker of post-operative organ dysfunction and future studies
are warranted to assess the role of NF-
κ
B in neutrophil activation
and organ dysfunction following surgery.
47
The activated
neutrophil plays a central role in sepsis (secondary or severe
systemic inflammation), which is often present in a patient post
vascular intervention. The importance of NF-
κ
B activation in
clinical sepsis has not been investigated in patients at risk of
lower limb amputations.
Growth factors
Studies have stressed the role of growth factors on the
development of NIH.
48
Several growth factors stimulate migration
and proliferation of medial SMCs into the neo-intima and are
released from activated platelets, leukocytes, local endothelial
cells and medial SMCs during the cellular proliferation phase of
NIH. Furthermore, the release of growth factors by inflammatory
cells in the vasculature specifically is of great importance, as
atherosclerosis is a chronic inflammatory disease. These growth
factors include vascular endothelial growth factor (VEGF),
platelet-derived growth factor A and B (PDGF A and B),
fibroblast growth factor (FGF) and insulin-like growth factor
(
IGF). The relationship of the latter factors to NIH is discussed
below.
VEGF:
VEGF is a glycoprotein that stimulates angiogenic
and vascular permeability-enhancing activities specific for
endothelial cells. The role of the members of the VEGF family in
NIH is unknown. Where a number of studies suggest that VEGFs
reduce NIH, others propose that they promote restenosis and
atherosclerosis. A study in rabbits demonstrated that the strongly
angiogenic VEGF-A, VEGF-D and VEGF-D
∆
N
∆
C
increased NIH
in the carotid artery, which correlated strongly with adventitial
angiogenesis.
49
In fact, several studies have linked adventitial
angiogenesis with restenosis.
50-52
VEGF-C-positive macrophages, which were present in the
early neo-intima in rats, were later found in the adventitia after its
removal, suggesting their involvement in adventitial lymphangio-
genesis.
53
This is of importance as it delivers and activates
inflammatory cells that release growth factors which, in turn,
promote neo-intimal infiltration and hyperplasia.
Apart from the ischaemic myocardium, the angiogenic effects
of VEGF-B are minimal in most organs and many recent
studies have described it as a potent neuroprotective factor.
54,55
Surprisingly, it has also been shown to play a role in modulating
endothelial fatty acid transportation.
56
Stefanadis
et al.
(2007)
showed a significant reduction in
neovessel growth and neo-intimal thickness in New Zealand
rats after four weeks of being treated with antibodies specific
for VEGF while on a atherogenic diet.
57
Whether the inhibition
of VEGF correlates with a reduced smooth muscle content or
has a direct anti-proliferative effect, has yet to be determined.
Nevertheless VEGF inhibition showed a possible favourable
effect on NIH.
An editorial by Simons (2009) summarised recent evidence
suggesting that the role of VEGF in neo-intimal formation
occurs in the adventitia.
52
Specifically, stent-induced damage
to the adventitia initiates the local inflammatory response, the
production of VEGF, which subsequently induces monocyte
chemo-attractant protein-1 (MCP-1) expression in medial
SMCs. This results in monocyte accumulation in the adventitia,
which also secretes VEGF, to further amplify the cascade that
ultimately leads to SMC phenotypic modulation, allowing
migration of SMC to the intima. This altered state of SMCs has
been established as a critical role in the pathogenesis of NIH.
58
PDGF-A, PDGF–B, IGF and FGF:
PDGF, IGF and FGF
are important regulators of angiogenesis, and vascular injury
increases the availability of many such growth factors. PDGF is
a crucial regulator of SMC proliferation and migration. Based on
the two polypeptide chains, A and B, different isoforms of PDGF
exist. It has been shown that SMCs from injured arteries only
secrete PDGF-A. However, such injury exposes these SMCs to
