doi: 10.1161/01.STR.0000054052.52510.2C
(Stroke. 2003;34:327.)
© 2003 American Heart Association, Inc.
Advances in Stroke 2002 |
Vascular Protection
From the Departments of Internal Medicine and Pharmacology, Cardiovascular Center, University of Iowa Carver College of Medicine, Iowa City.
Correspondence to Frank M. Faraci, PhD, Department of Internal Medicine, E315-GH, University of Iowa, Carver College of Medicine, Iowa City, IA 52242-1081. E-mail frank-faraci{at}uiowa.edu
Key Words: endothelium • nitric oxide • oxygen radical • superoxide dismutase
In contrast to the emphasis that has been placed on studies of neuroprotection, relatively few studies have addressed mechanisms of vascular protection in the cerebral circulation. Studies in this area have broad potential, because advances in our understanding of molecular mechanisms that contribute to and protect from vascular dysfunction could eventually lead to development of more effective therapies for cardiovascular disease. This editorial will highlight some recent advances related to vascular protection in brain.
Superoxide Dismutases
At relatively low concentrations, superoxide and other reactive oxygen species play important roles, including acting as mediators in signaling processes and regulation of gene expression. High levels of reactive oxygen species contribute to abnormal cell growth and vascular dysfunction. For example, there is recent evidence for increased superoxide in cerebral circulation after subarachnoid hemorrhage (SAH), in the presence of hyperhomocystinemia and diabetes, and in response to angiotensin II or alcohol.1–5
Local steady-state levels of superoxide are dependent on both the rate of superoxide production and activity of endogenous superoxide dismutases (SODs) (Figure). There are 3 isoforms of SOD (cytosolic or CuZn-SOD [SOD-1], mitochondrial or Mn-SOD [SOD-2], and extracellular CuZn-SOD [EC-SOD, SOD-3]), which are localized in distinct subcellular compartments (Figure). Although recent studies in nonvascular cells suggest that these different isoforms have major but distinctive roles,6 the functional importance of individual SOD isoforms has been unclear for any blood vessel.
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CuZn-SOD
The CuZn isoform of SOD is the predominant form of SOD in blood vessels, because it accounts for 50% to 80% of total SOD activity.7–9 Studies using gene-targeted mice indicate that CuZn-SOD deficiency increases superoxide throughout the vessel wall, impairs endothelium-dependent relaxation and nitric oxide (NO) signaling in carotid artery and cerebral microvessels, and selectively augments vasoconstrictor responses to serotonin, a key mediator of platelet-induced vasoconstriction.8 Increases in superoxide in cerebral arteries after treatment with arachidonate are greatly augmented after pharmacological inhibition of CuZn-SOD.10 These latter findings have broad implications, because metabolism of arachidonic acid is thought to be a major source of superoxide in brain under several pathophysiological conditions. Deficiency in CuZn-SOD also impacts vascular structure, because cerebral arterioles in CuZn-SOD–deficient mice undergo hypertrophy.11 These findings provide the first direct evidence that CuZn-SOD normally inhibits vascular hypertrophy and that this isoform of SOD plays a major role in regulation of cerebral vascular growth. Finally, overexpression of CuZn-SOD (using transgenic or gene transfer technology) is protective in a model of ceramide-induced endothelial dysfunction and in a model of fluid percussion injury that produces impairment of autoregulation.12,13 Thus, initial studies suggest that CuZn-SOD is a key isoform in relation to cerebral vascular biology.
Mn-SOD
Although the levels of Mn-SOD in blood vessels are relatively small,7,9 Mn-SOD may exert important functional effects in cerebral circulation, because endothelium expresses high levels of Mn-SOD14 and levels of Mn-SOD are higher in cerebral arteries than in extracranial arteries.15 The mitochondrial content of cerebral endothelium is greater than that in other cells,16 and high levels of Mn-SOD may be required to limit oxidative stress in the metabolically active cerebral endothelium (the blood-brain barrier).
Recent studies of Mn-SOD heterozygous–deficient mice (Mn-SOD+/-) on an apolipoprotein E–deficient background indicate that Mn-SOD protects against vascular mitochondrial DNA damage and development of atherosclerosis in aorta.17 Such findings suggest that studies focusing on the role of Mn-SOD in carotid artery disease may be insightful. With regard to the microcirculation, our preliminary studies indicate that endothelial function is impaired in cerebral arterioles from Mn-SOD+/- mice (Didion and Faraci, unpublished data, 2002).
Mn-SOD is unique among the SODs in that it is upregulated in response to oxidative stress because its promoter region contains response elements for the redox-sensitive transcription factors AP-1 and nuclear factor-
B, the latter being critical in regulation of many inflammatory-related genes. Thus, upregulation of Mn-SOD may be a key compensatory response to oxidative stress. Lipopolysaccharide and bacterial meningitis increase Mn-SOD expression in the cerebral vasculature.18,19 The functional importance of this upregulation of Mn-SOD during oxidative stress remains to be determined.
EC-SOD
Based on its subcellular localization and because EC-SOD is a major component of total SOD activity in blood vessels,7,9 it has been hypothesized that EC-SOD would protect NO as it diffuses through the vessel wall.9 The first study that addressed this hypothesis using EC-SOD–deficient mice reported a surprisingly modest role for EC-SOD with regard to endothelial function in the cerebral microcirculation.20 Studies using overexpression strategies have been more impressive, however, because increased expression of EC-SOD (produced using either gene transfer or transgenic technology) attenuates vasospasm after SAH.21,22
Nitric Oxide
NO influences cerebral vascular tone, is the primary mediator of endothelium-dependent relaxation in the cerebral circulation,23 and is thought to play key roles in regulation of vascular gene expression, cell growth, platelet aggregation, and leukocyte adhesion. Defining the role of specific isoforms of NO synthase (endothelial NOS [eNOS], neuronal NOS [nNOS], and inducible NOS [iNOS]) has sometimes been difficult, and recent studies suggest all isoforms of NOS are normally present within the wall of at least some blood vessels.24 The specific role for eNOS in inhibiting vasoconstrictor responses was tested recently using eNOS-deficient mice. eNOS deficiency was associated with enhanced constrictor responses of carotid arteries to serotonin, particularly in female mice.25 These results provided the first direct evidence that eNOS is a major determinant of vascular effects of serotonin but also suggested a gene-dosing effect of eNOS in relation to vasoconstrictor responses.
Pharmacological strategies are being developed to capitalize on protective effects of eNOS in the cerebral circulation. For example, upregulation of eNOS by statins confers protection from stroke, and a recent study demonstrated that a similar approach could be used to attenuate cerebral vasospasm and neurological deficits after SAH.26 Similarly, corticosteroids have been shown to rapidly enhance intraischemic cerebral blood flow and reduce cerebral infarct size via an eNOS-dependent mechanism.27
Peroxisome Proliferator Activated Receptors
Peroxisome proliferator activated receptors (PPARs) are ligand-activated transcription factors that have begun to receive considerable attention in studies of vascular biology.28,29 There are 3 subtypes of PPARs (PPAR
, PPARß/
, and PPAR
) that regulate gene expression by binding to PPAR-response elements in target genes. Emerging evidence, based on work with vascular cells in culture and in extracranial blood vessels, suggests that these transcription factors may exhibit multiple protective effects within the vessel wall, including antiinflammatory, antiatherogenic, and antihypertensive effects. For example, although initially thought to be restricted to adipose tissue, PPAR is now known to be expressed in both endothelium and vascular muscle. Activation of PPAR reduces the secretion of endothelin, decreases activation of nuclear factor-B and expression of adhesion molecules, and reduces expression of NAD(P)H oxidase (a major source of superoxide in vascular cells) and receptors for angiotensin II.28–30 Activators of PPAR increase levels of CuZn-SOD in cultured endothelium,30 suggesting one additional mechanism by which PPAR may exert protective effects within the vasculature (Figure).
Based on these characteristics, it was hypothesized that expression of PPAR in endothelium should exert protective effects on endothelial function. In preliminary studies in carotid artery in mouse models of chronic hypertension and type II diabetes,31,32 PPAR agonists improved endothelial function. Importantly, some of these initial findings suggest that beneficial effects may occur by actions of PPAR within the vessel wall.32 Thus, it will be of interest in future studies to define the physiological role of PPAR in the carotid artery and cerebral circulation and to determine how impairment of PPAR signaling may contribute to the pathophysiology of cerebral vascular disease.
Acknowledgments
Studies that are reviewed from our laboratory are supported by National Institutes of Health grants HL-62984, HL-38901, and NS-24621.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Stroke Association.
Received December 5, 2002; accepted December 11, 2002.
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