Abstract
Angiogenesis is the formation of new blood vessels from preexisting ones and is implicated in physiologic vascular development, pathologic blood vessel growth, and vascular restoration. This is in contrast to vasculogenesis, which is de novo growth of vessels from vascular precursors, or from vascular repair that occurs when circulating endothelial progenitor cells home into an area and develop into blood vessels. The objective of this review is to discuss the isoform-specific role of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) in physiologic and pathologic angiogenesis and vascular repair, but will not specifically address vasculogenesis. As the major source of reactive oxygen species (ROS) in vascular endothelial cells (ECs), NOX has gained increasing attention in angiogenesis. Activation of NOX leads to events necessary for physiologic and pathologic angiogenesis, including EC migration, proliferation and tube formation. However, activation of different NOX isoforms has different effects in angiogenesis. Activation of NOX2 promotes pathologic angiogenesis and vascular inflammation, but may be beneficial in revascularization in the hindlimb ischemic model. In contrast, activation of NOX4 appears to promote physiologic angiogenesis mainly by protecting the vasculature during ischemia, hypoxia and inflammation and by restoring vascularization, except in models of oxygen-induced retinopathy and diabetes where NOX4 activation leads to pathologic angiogenesis.
Highlights
Angiogenesis is the formation of new blood vessels from pre-existing ones [1] and includes physiologic vascularization [2,3], vascular restoration in response to ischemia and other stresses implicated in cardiovascular diseases [4,5], and pathologic neovascularization [6], such as that seen in tumor growth [7,8,9,10] and ocular diseases [6,11,12,13]
We provide an update of the new findings of NADPH Oxidase (NOX) in regulating physiologic and pathologic angiogenesis in ocular vascular diseases, cardiovascular diseases, and tumor angiogenesis, with emphasis on the roles of NADPH Oxidase 2 (NOX2) and NADPH Oxidase 4 (NOX4), which are best known in vascular diseases
Within isolectin-stained lesions compared to protein, cadherin, in the retinal pigment epithelial (RPE) [55]. This finding is supported by our study in mice with wild-type controls. These findings from our studies suggest promotes a deletion of p47phox to inhibit NOX2 enzymatic activity. p47phox−/− mice had smaller that pathologic in choroidal neovascularization and may translate neovascular andangiogenesis less DHE fluorescence, indicative of O2, within isolectin-stained
Summary
Angiogenesis is the formation of new blood vessels from pre-existing ones [1] and includes physiologic vascularization [2,3], vascular restoration in response to ischemia and other stresses implicated in cardiovascular diseases [4,5], and pathologic neovascularization [6], such as that seen in tumor growth [7,8,9,10] and ocular diseases [6,11,12,13]. In vascular ECs, activation of NOX isoforms is regulated through different signaling cascades that lead to ROS generation in the form of either the superoxide radical (O2 − ) or hydrogen peroxide (H2 O2 ). As oxidase activity of NOX2 requires assembly of membrane subunits with cytosolic subunits, a mutation or deletion of any subunit impairs ROS generation from the NOX2. Nox interacts with p22phox to form a membrane- bound complex and requires p22phox for activation. Cumulative evidence indicates that NOX-generated ROS can promote or inhibit angiogenesis depending in part on what signaling pathways are activated and in what cells, those that interact with vascular ECs or the ECs themselves. Important is the subcellular location of the NOX isoforms in cells and vascular ECs. In diabetic retinopathy, interactions between oxidative stress-related and inflammatory pathways appear important in pathologic neovascularization [35,36,37].
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