Reactive Oxygen Species in Physiologic and Pathologic Angiogenesis - Mechanical and Chemical Signaling in Angiogenesis - page 77

4 Reactive Oxygen Species in Disease—Effects
on Angiogenesis
ROS play a significant role in many vascular diseases, including atherosclerosis,
hypertension, diabetes and cancer among others [ 98 ]. Elevated ROS in these
conditions negatively affect a multitude of vascular functions. Endothelial cells
directly exposed to high ROS undergo apoptosis, and chemically-induced apop-
tosis through oxidized LDL, angiotensin II, high glucose, and tumor necrosis
factor-a is inhibited by antioxidants such as superoxide dismutase and N-acetyl
cysteine [ 99 ]. ROS enhance inflammatory adhesion molecule expression
[ 100 , 101 ]. ROS, especially superoxide, inactivate nitric oxide to inhibit endo-
thelium-dependent vasodilation [ 102 ]. In addition, individuals who suffer from
these diseases may have altered angiogenesis.
ROS are important in all stages of atherosclerosis, from atherosclerotic plaque
formation to plaque rupture to the intervention response. Angiogenesis related to
elevated ROS may also play a role, since atherosclerotic vessels have intimal
microvasculature whereas in normal vessels the microvasculature is confined to
the adventitia [ 103 ]. These vessels may assist in plaque growth by recruiting
inflammatory cells or providing essential nutrients [ 104 ]. Both mechanical and
chemical factors may increase ROS to promote this angiogenesis. While laminar
shear stress produced a transient prooxidant signal that is quickly decreased by
antioxidant enzyme upregulation, the oscillatory shear stress present in athero-
sclerotic regions activated NADPH without compensatory SOD upregulation
[ 105 ]. Hypercholesterolemia [ 106 ] and oxidized lipids [ 107 ] activate PKC and
increase vascular ROS formation via NADPH oxidase [ 108 , 109 ]. The importance
of angiogenesis in atherosclerotic lesion progression is supported by reduced
plaque growth and intimal neovascularization with anti-angiogenic therapy [ 110 ].
Plaque rupture correlates with angiogenesis, with a higher prevalence of plaque
neovascularization measured clinically in lesions with plaque rupture [ 111 ]. Since
angiogenesis requires proteases, plaque angiogenesis could directly contribute to
plaque disruption [ 112 , 113 ]. In fact, nonatherosclerotic explanted human coronary
arteries showed homogenous low superoxide levels, whereas atherosclerotic
arteries had increased superoxide in the vulnerable plaque shoulder [ 114 ]. Finally,
baboon balloon-injured arteries demonstrated increased VEGF expression in the
neointima, which correlated with the lipid peroxidation product 4-hydroxynonenal,
an endogenous ROS present in atherosclerotic lesions [ 115 ].
All types of hypertension exhibit oxidative stress, which is important in
hypertensive pathogenesis [ 116 ]. In the most direct ROS effect, NADPH
oxidase-produced superoxide inactivates nitric oxide, thus inhibiting endothelium-
dependent vasodilation and increasing peripheral resistance [ 117 ]. A number of
hypertensive factors upregulate NADPH oxidases. Angiotensin II, an important
prohypertensive agent, induces and activates NADPH oxidases [ 118 ]. Knockout of
specific NADPH oxidase components prevented angiotensin II-induced stimula-
tion of superoxide, which in turn enhanced nitric oxide availability and attenuated