Biomedical Engineering Reference
In-Depth Information
As the extracellular matrix breaks down, it releases additional growth factors that
were bound to heparan sulfate proteoglycans. Concurrently, matrix protein break-
down products such as the plasminogen fragment angiostatin and the collagen XVIII
fragment endostatin, inhibit angiogenesis [ 1 ]. This balance prevents angiogenesis
from proceeding unchecked.
Reactive oxygen species (ROS) also help maintain this angiogenic balance.
Whereas low ROS levels stimulate angiogenesis and are in fact required for many
angiogenic signaling pathways, high ROS levels inhibit angiogenesis and promote
death of many cell types critical to the angiogenic process [ 2 ]. In addition to dose,
timing and application mode may also influence whether ROS are pro- or anti-
angiogenic. Antioxidant therapies to inhibit ROS and shift the angiogenic balance
have met with limited success, perhaps due to the complexity of ROS effects on
angiogenesis [ 3 ].
In cells, most ROS are formed as by-products of mitochondrial electron
transport. ROS can also be formed by NADPH oxidase, xanthine oxidase, and
nitric oxide synthase, among others [ 2 ]. Along with promoting angiogenesis, ROS
increase endothelial cell permeability, enhance cell adhesion molecule surface
expression, inhibit endothelial cell dependent vasodilation, and at large doses
induce apoptosis [ 4 ]. While ROS are important in a variety of physiological
processes, basal ROS levels are altered by many diseases including atheroscle-
rosis, hypertension, diabetes and cancer [ 5 - 7 ]. Interestingly, angiogenesis also
plays a critical role in many of these diseases.
In this chapter, we review biologically relevant reactive oxygen species and
their role in initiating angiogenic processes and acting as messengers for intra-
cellular angiogenic signaling. We then discuss how altered ROS levels in disease
affect angiogenesis. Finally, we describe new methods to apply ROS to promote
angiogenesis.
2 Reactive Oxygen Species
ROS are highly reactive molecules or free radicals derived from molecular oxygen
(O 2 ) (Fig. 1 ). Superoxide (O 2 - ) is formed by one electron reduction of O 2 by a
variety of enzymes including NADPH oxidase. Singlet oxygen (O 2 ( 1 D g )) is the
electronically excited state of O 2 (( 3 R g - ) 3 O 2 ), in which the two unpaired electrons
adopt antiparallel spins in the same orbital [ 8 ]. Oxygen reduction by two electrons
forms hydrogen peroxide (H 2 O 2 ), which is catalyzed by superoxide dismutase. The
hydroxyl radical (OH ) is produced by tri-electron reduction of O 2 in the presence
of metal ions through the Fenton reaction. ROS, especially hydroxyl radicals,
interact with amino acids and proteins to form longer lived organic hydroperoxides
(RO , ROO )
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