Biomedical Engineering Reference
In-Depth Information
originate from many cell types including tumor cells, fibroblast, keratinocytes and
macrophages [
37
]. Up-regulation of pro-angiogenic factors and the simultaneous
down-regulation of endogenous angiogenesis inhibitors are normally triggered
when the tissue environment becomes hypoxic [
38
,
39
] or inflammatory [
40
].
Oxygen sensing is important for many biological processes including development,
pH homeostasis and angiogenesis [
41
]. Critical molecular mediators of hypoxia and
cellular oxygen-signaling pathways, hypoxia-inducible factor (HIFs), are known to
directly activate the expression of such pro-angiogenic factors as VEGF, PDGF-B,
Ang-1, Ang-2 and receptors VEGFR-1, VEGFR-2 and Tie-2 [
39
,
42
], (see also
Table
1
). In particular, hypoxia induces a dramatic increase in VEGF messenger RNA
levels [
43
]. VEGF is essential for embryonic vasculogenesis and angiogenesis, as
demonstrated by the observation that VEGF gene inactivation is lethal [
44
,
45
].
In vitro, VEGF promotes EC proliferation, migration, differentiation and capillary
formation. It is also widely appreciated that tumor cells secrete angiogenesis-related
proteins under hypoxic conditions [
46
,
47
]. Recently, a linear correlation was estab-
lished between hypoxic growth conditions and the expression levels of eight angio-
genesis-related proteins including VEGF, IL-8, PDGF-AA, PDGF-AA/BB, TGF-b1,
TGF-b2, EGF, and IP-10 [
48
]. In addition, stromal cells promote angiogenesis [
49
,
50
]
and also enhance vascular maturation [
51
].
Inflammatory cytokines and chemokines represent another group of signaling
molecules with critical roles in angiogenesis regulation during tumor growth, wound
healing and ischemia [
40
]. Furthermore, chronic inflammatory conditions such as
rheumatoid arthritis (RA) are considered as angiogenic diseases, as the excessive
neovascularization contributes to their pathogenesis. Pro-inflammatory factors such
as TNF-a, IL-8/CXCL8 and SDF-1/CXCL12 are known angiogenic mediators while
IL-4, LIF and PF4/CXCL4 exert an inhibitory role [
52
,
53
]. For extensive reviews on
additional topics related to angiogenesis in inflammation see [
54
].
2.3 Angiogenesis in Disease Processes
In healthy adults, endothelial cells remain virtually quiescent—the result of a strict
balance between pro- and anti-angiogenic factors. The transition from a quiescent
to an angiogenic phenotype occurs when this balance is disrupted and pro-
angiogenic factors dominate. While physiologic angiogenesis occurs in a tightly
regulated fashion, deregulation of this process contributes to the progression of a
variety of diseases (Table
2
). The pathogenesis of the diseases may be charac-
terized by either an excessive or insufficient growth of blood vessels. Interestingly,
while the cellular and molecular regulators of normal and pathological angio-
genesis have much in common, the latter is characterized by uncontrolled, aberrant
vascular growth [
55
]. For example, VEGF signaling plays a pivotal role in normal
and tumor angiogenesis, however tumor vasculature is chaotic and structurally
abnormal [
55
].
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