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EDITORIAL FOCUS
dilates cerebral arteries via NAD(P)H oxidase-dependent Ca2+ spark activation"
Department of Pharmacology, The University of Melbourne, Parkville, Victoria, Australia
OXIDATIVE STRESS IN THE VASCULATURE involves chronically elevated, uncontrolled levels of reactive oxygen species (ROS) and is thought to contribute to vascular dysfunction associated with many cardiovascular diseases, including hypertension and atherosclerosis (5). This point notwithstanding, growing evidence indicates that when generated acutely at lower levels and in a regulated manner, ROS may serve as important physiological cell signaling molecules that modulate various aspects of vascular function, including smooth muscle tone (13).
The parent ROS molecule, O2–·, can be generated by a range of vascular oxidases via the one-electron reduction of molecular O2. This highly reactive and toxic molecule can react with and inactivate the vasoprotective nitric oxide, forming another harmful species, ONOO–. Alternatively, O2–· can either be dismutated spontaneously or catalyzed by SOD to form the more stable and cell-permeable ROS, H2O2. Emerging evidence suggests that H2O2 might be the most important cell-signaling ROS molecule in vascular cells (4). Indeed, with respect to the regulation of vascular tone (and hence local blood flow), H2O2 can elicit vasorelaxation (9), and in some vascular beds there is evidence that H2O2 itself may serve as an endothelium-derived hyperpolarizing factor (16).
Importantly, H2O2 appears to be a particularly powerful cerebral vasodilator, both in vitro and in vivo (9, 13, 14, 20), and increasing evidence supports its physiological relevance. For example, the generation of endogenous H2O2 in the cerebral artery wall in vivo fully mediates the vasodilatory effects of both bradykinin and arachidonate in rat pial arterioles (17, 18) and partially mediates flow-dependent dilatation of the rat basilar artery (15). Furthermore, ANG II-induced vasoconstriction appears to be selectively weaker in cerebral vs. systemic arteries as a result of the counteracting vasorelaxant effect of endogenous H2O2 (13). Thus the findings of an increasing number of studies suggest that O2–· generated after activation of major enzymatic sources, such as cyclooxygenases (18), NAD(P)H oxidases (13, 15), and mitochondria (21) by pathophysiologically relevant stimuli can be converted to H2O2 efficiently, leading to cerebral vasodilatation.
Research conducted during the past decade has revealed that a major mechanism underlying H2O2-induced cerebral vasodilatation is the hyperpolarization of vascular smooth muscle cells as a result of K+ efflux after the activation of K+ channels (9, 14, 17, 18). Located in the plasma membrane, large-conductance, Ca2+-activated K+ (KCa) channels are sensitive to local increases in cytosolic Ca2+ concentration ([Ca2+]i) as their name suggests, and their open probability is greatly increased by Ca2+ sparks released from closely localized ryanodine-sensitive Ca2+ release (RyR) channels in the sarcoplasmic reticulum (SR). Plasma membrane hyperpolarization then results in reduced activity of voltage-operated Ca2+ channels, lowering of global [Ca2+]i, and vascular muscle cell relaxation (10). Thus, intriguingly, although vascular smooth muscle cell relaxation occurs when global [Ca2+]i decreases, the powerful KCa channel-mediated mechanism of relaxation first depends on transient focal increases in Ca2+ levels, or Ca2+ sparks, that do not affect global [Ca2+]i.
Recently, Jaggar's group (6, 21) reported that either exogenous H2O2 or ROS derived from mitochondria can activate Ca2+ sparks from the SR, leading to KCa channel-mediated cerebral vasodilatation that can be blocked by the H2O2 scavenger catalase, suggesting that vascular RyR channels are redox-sensitive and can be activated by H2O2 (19). Therefore, an emerging concept, at least regarding the cerebral circulation, is that even in nondiseased vessels, the acute activation of any O2–·-generating system may lead to a powerful vasodilatory response mediated by H2O2-induced KCa channel activation. The recent finding that the activity and expression of NAD(P)H oxidase, perhaps the major vascular source of O2–·, is 10–100 times higher in cerebral vs. systemic arteries (13) also seems compatible with a prominent role for ROS-mediated acute vasodilatation in the cerebral circulation that potentially could be beneficial for and not detrimental to cerebral perfusion, at least in the short term. However, to clarify the importance of such a ROS-mediated cerebral vasodilator mechanism, the identification of endogenous stimuli that use it would be helpful.
Proinflammatory cytokines such as TNF-
have been associated with the development of atherosclerotic lesions and consequent cardiovascular events (11). TNF--induced vascular cell injury is thought to be mediated through its ability to promote intracellular ROS formation whereby it can activate NAD(P)H oxidase (8). TNF- is known to be generated during brain injury and stroke; however, interestingly, controversy exists regarding its role in stroke outcome, with both beneficial (3) and detrimental (1) effects having been proposed. Furthermore, TNF- is reported to constrict (12) and to dilate (2) cerebral arteries.
The article by Cheranov and Jaggar (see Ref. 7, p. C964 of this issue) elegantly identifies TNF- as one endogenous mediator that can elicit cerebral vasodilator responses via ROS-induced Ca2+ spark activation. Specifically, they report evidence that within just a few minutes, TNF- activates cerebrovascular NAD(P)H oxidase, resulting in the generation of H2O2, which increases SR Ca2+-ATPase spark frequency and activates KCa channels, leading to reduced global [Ca2+]i and subsequent cerebral vasodilatation. Thus their findings reveal that a mediator such as TNF-, which is thought to be harmful in terms of long-term vascular disease development, nevertheless can acutely cause cerebral vasodilatation. The significant strengths of this study include the use of TNF- as a defined and endogenously relevant stimulus of ROS signaling in vascular smooth muscle cells, the efficacious and selective effects of the pharmacological inhibitors used, and the combined application of several cutting-edge techniques, including laser-scanning confocal Ca2+ microscopic imaging, patch-clamp electrophysiology, fluorescence imaging for the detection of ROS in arterial segments, and diametric measurement of pressurized cerebral arteries.
Recent evidence indicates that NAD(P)H oxidase-derived ROS may play a greater vasodilatory role in the cerebral circulation during chronic hypertension (14). Similarly, Cheranov and Jaggar (7) postulate that after ischemia and stroke, TNF--induced ROS production, Ca2+ spark activation, and cerebral vasodilatation would be expected to be helpful rather than harmful in supporting local blood supply to the affected brain region. Hence, their data reinforce the new concept that in the cerebral circulation, H2O2 derived from NAD(P)H oxidase activity may represent an important mechanism of acutely increasing blood flow in healthy individuals and potentially in disease states (13). If so, caution may be needed in the future application of therapies to inhibit the effect of ROS in systemic vascular disease so that cerebral blood flow is not compromised inadvertently.
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