Redox signaling in vascular angiogenesis1,2 1Guest Editor: Toshikazu Yoshikawa 2This article is part of a series of reviews on “Vascular Dysfunction and Free Radicals.” The full list of papers may be found on the homepage of the journal (original) (raw)
Related papers
Reactive oxygen species promote angiogenesis in the infarcted rat heart
International Journal of Experimental Pathology, 2009
Angiogenesis is the formation of new capillary blood vessels from existent microvessels. It plays a critical role in various biological processes, such as wound healing, embryological development, the menstrual cycle, inflammation and the pathogenesis of various diseases, such as cancer, diabetic retinopathy and rheumatoid arthritis. Promoting angiogenesis in some circumstances can be beneficial. For example, promotion of angiogenesis can aid in accelerating various physiological processes and treatment of diseases requiring increased vascularization, such as the healing of wounds, INTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY
Potentiation of angiogenic response by ischemic and hypoxic reconditioning of the heart
Journal of Cellular and Molecular Medicine, 2002
This review is intended to discuss the newly discovered role of preconditioning which should make it an attractive therapeutic stimulus for repairing the injured myocardium. We recently found that apart from rendering the myocardium tolerant to ischemic reperfusion injury, preconditioning also potentiates angiogenesis. Our study demonstrated for the first time that both ischemic and hypoxic preconditioning triggered myocardial angiogenesis at the capillary and arteriolar levels which nicely corroborated with the improved myocardial contractile function. Hypoxic preconditioning resulted in the stimulation of VEGF, the most potent angiogenic factor known to date. In concert, endothelial cell specific tyrosine kinase receptors, Tie 1, Tie 2 and Flt-1 and Flk-1 were also significantly enhanced in the preconditioned myocardium. The redox-regulated transcription factor NFkB was found to play an essential role in the preconditioning regulation of angiogenesis.
Journal of Biological Chemistry
Endothelial cell-derived oxygen free radicals are important mediators of postischemic injury; however, the mechanisms that trigger this radical generation are not known, and it is not known if this process can occur in human cells and tissues. The enzyme xanthine oxidase can be an important source of radical generation; however, it has been reported that this enzyme may not be present in human endothelium. To determine the presence and mechanisms of radical generation in human vascular endothelial cells subjected to anoxia and reoxygenation, electron paramagnetic resonance measurements were performed on cultured human aortic endothelial cells using the spin trap 5,5-dimethyl-l-pyrroline N-oxide (DMPO). These measurements were correlated with cellular injury, xanthine oxidase activity, and alterations in cellular nucleotides. Upon reoxygenation after 60 min of anoxia, large DMPO-OH (aN = a, = 14.9 G) and smaller DMPO-R signals were seen. Superoxide dismutase totally quenched this radical generation. The ferric iron chelator deferoxamine prevented cell death and totally quenched the DMPO-R signal with a 40% decrease in the DMPO-OH signal. Xanthine oxidase was shown to be present in these cells and to be the primary source of free radicals. While the concentration of this enzyme did not change after anoxia, the concentration of its substrate, hypoxanthine, markedly increased, resulting in increased free radical generation upon reoxygenation. Thus, reoxygenated human vascular endothelial cells generate superoxide free radicals, which further react with iron to form the reactive hydroxyl radical, which in turn causes cell death. Xanthine oxidase was the primary source of radical generation with this process triggered by the breakdown of ATP to the substrate hypoxanthine during anoxia.
Toxicology, 2000
Introduction: Oxidative stress, as exerted by free radicals within biological systems, is known to exert numerous physiological and pathological effects on the cardiovascular system. Short-term exposure to environmental conditions such as low oxygen tension can cause such oxidative stress in vivo through inhalational hypoxia/reoxygenation. In this report the effects of different durations of hypoxia were investigated on myocardial protein expression of vascular endothelial growth factor (VEGF), a major angiogenic growth factor, and also explore the possible modulatory role of transcription factor NFkB on such expression. Methods: Forty eight male Sprague -Dawley rats (300 g b.w.) were randomly divided into four groups and subjected to either 1, 2 or 4 h of systemic normobaric hypoxemic hypoxia (10 90.4% O 2 ) in an anesthesia chamber, or to 4 h of normoxia (ambient 20.9 9 0.4% O 2 ) to time-match the maximal hypoxic duration. All rats were then kept under normoxic conditions. Rats were sacrificed and hearts harvested either after 2 h for later electrophoretic mobility gel shift assay for NFkB, or after 24 h for later Western blot analysis for VEGF. Results: Western blot analysis for VEGF revealed significantly elevated protein expression (2.4-fold compared to baseline control) in the 1 h group. This elevated level persisted in the 2 and 4 h groups as well. Two hours post-hypoxia gel shift assay for NFkB indicated significant nuclear translocation and DNA binding of this transcription factor in the 1 and 2 h groups, with moderate decrease in the 4 h group. Conclusion: In vivo oxidative stress caused by systemic inhalational hypoxemic hypoxia increases cardiac VEGF protein expression and may trigger myocardial angiogenesis. The results suggest that NFkB modulates such an effect.
Control of angiogenesis dictated by picomolar superoxide levels
Free Radical Biology and Medicine, 2013
Control of vascular insufficiencies due to various cardiovascular pathologies is important for developing specific and effective treatments. Fluctuations in oxidative stress significantly alter the progression of angiogenesis under physiological and pathological conditions. However, the precise amount of reactive oxygen species (ROS) required to influence subsequent signaling pathways for ischemic angiogenesis remain undefined. Here, we have determined the effect of ROS mediated molecular mechanisms on angiogenesis in a murine model of peripheral artery disease using Gclm mutant mice (a model of compromised glutathione synthesis, therefore reduced antioxidant capacity). Left femoral artery ligation and excision were performed in Gclm WT (+/+), heterozygous (+/−), and null (−/−) mice. Blood flow (laser Doppler), angiogenic index (CD31/DAPI) and proliferation index (Ki67/DAPI) were significantly increased in Gclm +/− mice but not in Gclm +/+ or Gclm −/− mice. Measurements of reactive oxygen species suggest that the amount of superoxide required to stimulate angiogenesis following the induction of ischemia is 9.82 pmol/mg of tissue. Protein carbonyl levels increased in a manner consistent with increasing oxidative stress. Superoxide and protein carbonyl levels were reduced by the addition of the nitroxide tempol, a known superoxide dismutase mimetic. Finally, restoration of blood flow in Gclm +/− mice was attenuated by a VEGF 164 aptamer verifying that slightly elevated levels of ROS restore blood flow by stimulating endothelial cell proliferation through a VEGF dependent pathway. The results of this study reveal new information on the amount of ROS necessary for angiogenic activity and provide the foundation of critical redox parameters for vascular remodeling responses. The information obtained from this study on vascular ischemia, using a model of decreased antioxidant capacity, has provided insight into the control of revascularization and is a step forward in our ability to regulate angiogenic therapies.
Stem cells international, 2017
Endothelial colony forming cells (ECFCs) have shown a promise in tissue engineering of vascular constructs, where they act as endothelial progenitor cells. After implantation, ECFCs are likely to be subjected to elevated reactive oxygen species (ROS). The transcription factor Nrf2 regulates the expression of antioxidant enzymes in response to ROS. Stable knockdown of Nrf2 and Keap1 was achieved by transduction with lentiviral shRNAs; activation of Nrf2 was induced by incubation with sulforaphane (SFN). Expression of Nrf2 target genes was assessed by qPCR, oxidative stress was assessed using CM-DCFDA, and angiogenesis was quantified by scratch-wound and tubule-formation assays Results. Nrf2 knockdown led to a reduction of antioxidant gene expression and increased ROS. Angiogenesis was disturbed after Nrf2 knockdown even in the absence of ROS. Conversely, angiogenesis was preserved in high ROS conditions after knockdown of Keap1. Preincubation of ECFCs with SFN reduced intracellular R...