Serial review: vascular dysfunction and free radicalsRedox signaling in vascular angiogenesis1, 2
Introduction
Reactive oxygen species (ROS) are implicated in the pathophysiology of a variety of vascular diseases, including coronary artery disease, arrhythmias, congestive heart failure, cardiomyopathy, hypertension, atherosclerosis, and diabetes [1], [2]. The presence of massive amount of ROS in the diseased tissues has been confirmed directly by identifying cytotoxic hydroxyl radical (OH•) and indirectly by measuring the products of lipid peroxidation as well as protein and DNA breakdown [3], [4]. Constitutive cellular protection against oxidative stress is provided by various intracellular antioxidants, such as glutathione, α-tocopherol, ascorbic acid, and antioxidant enzymes that include superoxide dismutase (SOD), catalase, and glutathione peroxidase (GSHPx) [5], [6]. There is evidence that oxidative stress resulting from increased production of ROS causes a reduction of intracellular antioxidants in the vascular organs [7], [8]. Pretreatment of the hearts with antioxidants or antioxidant enzymes has been found to ameliorate ischemic reperfusion injury by reducing the formation of ROS [9], [10].
Short exposure to hypoxia/reoxygenation, either directly or indirectly, produces oxidative stress, which is associated with angiogenesis or neovascularization. This process is thought to be regulated by several growth factors (endothelial growth factor [EGF], transforming growth factor [TGF]-α, b-fibroblast growth factor [FGF], vascular endothelial growth factor [VEGF]). Induction of these angiogenic factors are triggered by various stress responses. For example, tissue hypoxia exerts its proangiogenic action through various angiogenic factors, the most notable being VEGF, which has been associated mainly with initiating the process of angiogenesis through the recruitment and proliferation of endothelial cells [11]. Brief exposure to hypoxia (30–60 min) followed by reoxygenation, significantly accelerated (3-fold) the rate of tubular morphogenesis. We, as well as others, found that hypoxia followed by reoxygenation and not hypoxia alone caused the formation of ROS and the activation of redox-regulated transcription factor NFκB, both of which were inhibited by ROS-scavengers [11], [12]. Tubular morphogenesis was inhibited by ROS antagonists in a dose-dependent manner. In the clinical setting of hypoxia/reoxygenation enhanced activation of ROS may trigger intracellular signaling that might accelerate neovascularization in vivo. In fact, we observed that hypoxic bursts of 5–10 min duration followed by reoxygenation (ischemic or hypoxic preconditioning) led to myocardial angiogenesis in rat myocardial infarction model [13], [14]. Use of antioxidant such as dimethyl thiourea (DMTU) inhibited preconditioning-mediated myocardial angiogenesis (unpublished data). Our laboratory has not only shown the production of the OH• radical during reperfusion of ischemic rat heart, but also demonstrated the production of the OH• radical in the hearts of patients undergoing coronary bypass surgery [15].
The ROS-mediated angiogenic response was also observed in several other previous studies. The administration of EGB-761, an antioxidant derived from Ginkgo biloba leaves, was found to inhibit lymphocyte-induced angiogenesis suggesting a role of ROS in angiogenesis [16]. The evidence that T cell response requires the action of oxygen free radicals [17] further supports the role of ROS in angiogenesis. Another related study showed that thiol-containing compounds could inhibit the production of macrophage-mediated angiogenic activity [18]. Monocyte or macrophage-derived angiogenesis was inhibited by oxygen free radical scavengers [19]. Another recent study demonstrated that H2O2 is directly involved in lymphocyte activation of angiogenic response [20].
It thus appears that after causing injury to the cells, ROS promptly initiate the tissue-repair process by triggering angiogenic response. Dichotomy in ROS behavior can be explained in light of recent findings that ROS can function as signaling molecules. Evidence is rapidly accumulating to indicate that ROS can initiate a cascade of signal transduction process. Nitric oxide (NO) is a typical example. It has been reported that during myocardial adaptation to ischemia, NO plays a crucial role by initiating a cascade of signal transduction processes [21]. ROS have also been found to function as signaling molecules during myocardial preconditioning against oxidative or hypoxic stress [22].
Many antioxidants can also function as signaling molecules, for example, polyphenolic antioxidants, such as proanthocyanidins and resveratrol [23], [24]. These compounds have been found to trigger a survival signal to the cells by reducing proapoptotic factors such as Jnk and c-Jun. It seems likely that antiangiogenic properties of thiol-containing antioxidants are due to their ability to counteract the angiogenesis process triggered by ROS. This mini review will focus on the role of ROS signaling in the mediation of angiogenenic response to the vascular cells.
Section snippets
Direct evidence: role of H2O2
ROS play a significant role in a variety of disease processes such as, heart attack, stroke, arthritis, circulatory shock, and inflammatory disease, etc. [25]. ROS have also been implicated in ischemic and reperfusion injury to a large variety of tissue [26]. The development of oxidative stress achieved by exposing the cells to low concentrations of H2O2 is a well-established technique. High concentration of H2O2 (250–1000 μM) causes endothelial cell injury [27]. However, a lower concentration
ROS signaling in angiogenic response
Various organs possess a remarkable ability to adapt themselves to any stressful situation by increasing resistance to the adverse consequences. Creating several stress situations, such as repeated ischemia and reperfusion (ischemic preconditioning) or repeated hypoxic stress followed by reoxygenation (hypoxic preconditioning), enables tissues such as heart to meet the subsequent stress challenge by upregulating their cellular defense through the enhancement of intracellular mediators (e.g.,
Role of NFκB
Evidence is rapidly accumulating to indicate that oxidative stress/free radicals lead to the activation of NFκB, which in turn induces the expression of genes [74]. NFκB is an inducible transcription factor. In vitro studies already documented the involvement of this transcription factor in tubular morphogenesis of human microvascular endothelial cells by oxidative stress [36]. The H2O2-induced tubular morphogenesis in HUVEC was blocked by the coadministration of NFκB antisense
Role of NO
NO plays a significant role in intracellular signaling process in cardiovascular as well as in other systems. NO is a unique messenger in that it is produced in one cell and diffuses into adjacent target cells to activate cytosolic guanylatecyclase-bound heme to generate the NO-heme adduct of guanylate cyclase. NO can readily react with other cellular hemoproteins such as hemoglobin and myoglobin to produce corresponding NO-heme adducts, which can rapidly activate guanylate cyclase [81], [82],
Role of cytokines
Evidence suggested the involvement of ROS in cytokine-mediated cell signaling. H2O2 was found to stimulate IL-8 production in cultured endothelial cells to the extent that modulated tubular morphogenesis [36]. In a separate study, lipid peroxidation and certain lipid peroxidation products were found to induce fibrogenic cytokines [99]. Therefore, we feel cytokine-mediated cellular signaling involves ROS. Several studies suggested that cytokines play a pivotal role in many biological processes,
ROS signaling and angiogenic gene expression
The most potent angiogenic gene VEGF expression was found to be upregulated by various factors, such as adenosine, cyclic adenosine monophosphate (cAMP) analogs, TNFα, IL-1β as well as by growth-promoting agents [110], [111], [112]. Hypoxia has been found to be a strong inducer for VEGF expression both in vivo and in vitro [42], [47]. bFGF mRNA was found to be increased also in the brains of animals exposed to hypoxia [113]. H2O2-mediated strong VEGF gene expression was also demonstrated in the
Antideath signal during ROS signaling of angiogenic response
Death signal to the cells is usually carried out in a programmed manner through a cascade of signal transduction steps leading to caspase activation. The final execution step occurs through apoptosis. Interestingly, free radicals and/or oxidative stress are common mediators of apoptosis, via the formation of lipid peroxidation and lipid hydroperoxide [119]. A direct role of oxygen free radicals has been implicated in the pathogenesis of apoptosis. For example, SOD or an expression vector
Summary and conclusion
It should be clear from the above discussion that ROS play a crucial role in vascular angiogenesis. Both in vitro and in vivo studies indicate that angiogenic response in vascular tissue is triggered by ROS signaling in a highly coordinated manner. It appears that massive amounts of ROS produced during ischemia and reperfusion in the vascular tissue, especially in heart, cause significant injury to the cardiomyocytes and endothelial cells. However, during the reperfusion, the same ROS
Acknowledgements
The study was supported in part by National Institutes of Health grants HL 56803, HL 22559, and HL 33889
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Guest Editor: Toshikazu Yoshikawa
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This 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.