Reactive Oxygen Species in Physiologic and Pathologic Angiogenesis - Mechanical and Chemical Signaling in Angiogenesis - page 78

hypertension [ 119 , 120 ]. Hypertensive oxidative stress inhibits angiogenesis and in
fact leads to microvascular rarefaction, the disappearance of capillaries and
pre-capillary arterioles. Rarefaction, a hallmark of hypertension, can occur when
elevated blood pressure causes capillary endothelium dysfunction, followed by
microvessel constriction and disappearance [ 121 ]. Microvascular rarefaction
increases peripheral resistance, thereby reducing blood flow and further elevating
blood pressure. Furthermore, impaired angiogenesis in development may predis-
pose to hypertension in later life [ 122 , 123 ]. Some new angiogenesis inhibitor
drugs used to treat cancer lead to hypertension through endothelial dysfunction and
capillary rarefaction [ 124 , 125 ], and vasodilator antihypertensive treatments
(particularly angiotensin converting enzyme inhibitors) can improve capillary
density [ 126 ]. Thus hypertension may systematically elevate vascular oxidative
stress to inhibit angiogenesis.
A wide variety of cancers have been linked to oxidative stress, including breast,
liver, lung, and skin cancer [ 127 - 130 ]. Human cancers produced hydrogen per-
oxide at levels comparable to activated neutrophils, and H 2 O 2 was involved in
lymphocyte-mediate angiogenesis in tumors [ 51 , 131 ]. Oxidative stress may
initially induce DNA damage leading to tumor formation. Subsequently, ROS may
promote cancer cell survival by activating Akt, or increase cell proliferation via
MAPK and NF-jB[ 132 - 135 ]. Angiogenesis is critical to tumor growth and
metastasis, and a number of cellular stress factors, including ROS, are important
angiogenic stimuli in cancer [ 136 ]. ROS stabilized HIF-1a and induced angiogenic
factor production by tumor cells [ 137 ]. The importance of ROS in tumor angio-
genesis is supported by the fact that antioxidants attenuated angiogenesis due to
tumor secreted products [ 138 ].
In diabetes, vascular ROS are increased due to both high glucose and advanced
glycation end products (AGE). High glucose leads to superoxide leakage from
mitochondrial respiration, increases NADPH oxidase activity in endothelial cells
through the PKC pathway, and upregulates NAPDH oxidase expression [ 139 - 141 ].
AGE increased NADPH oxidase expression in cardiac myocytes [ 142 ], and down-
regulation of NADPH oxidase attenuated endothelial cell activation in response to
AGE [ 143 ]. Blood vessels from diabetic subjects showed increased ROS due to
enhanced NADPH oxidase activity and subsequent eNOS uncoupling [ 144 - 146 ].
Interestingly, angiogenesis in diabetes is vascular-bed dependent. Excess angio-
genesis in renal glomeruli leads to loss of renal filtration function and diabetic
nephropathy. Fragile new capillaries formed due excessive angiogenesis in the eye
create a unique retinopathy [ 147 ]. In contrast, reduced angiogenesis in the extrem-
ities contributes to poor wound healing [ 148 ]. While no direct link has been shown,
there is strong correlation between ROS production, neovascularization and VEGF
expression in eyes of diabetics [ 149 , 150 ]. This correlation is supported by the fact
that antioxidants inhibited neovascularization in the mouse model [ 151 , 152 ]. ROS
dose and timing are particularly important in wound healing [ 32 ]. High ROS levels
are initially produced at the wound site to prevent wound infection. As the wound
progresses out of the inflammatory phase and into the proliferative phase, lower ROS
levels initiate wound healing processes, especially angiogenesis [ 32 ]. However,