Microfluidic Devices for Angiogenesis - Mechanical and Chemical Signaling in Angiogenesis - page 96

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 ].