Donate Help Contact The AHA Sign In Home
American Heart Association
Stroke
Search: search_blue_button Advanced Search
« Previous Article | Table of Contents | Next Article »
Stroke. 2003;34:327-329
doi: 10.1161/01.STR.0000054052.52510.2C
This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Faraci, F. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Faraci, F. M.

(Stroke. 2003;34:327.)
© 2003 American Heart Association, Inc.

Advances in Stroke 2002

Vascular Protection

Frank M. Faraci, PhD

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.



View larger version (21K):
[in this window]
[in a new window]
  		Schematic illustration of how superoxide (O2-) is dismuted by the 3 superoxide dismutases (CuZn-SOD, Mn-SOD, and EC-SOD) to H2O2. NO is produced by eNOS and normally diffuses out of endothelium to react with its major molecular target, soluble guanylate cyclase. NO can also rapidly react with superoxide to form peroxynitrite (ONOO-). PPAR{gamma} is hypothesized to have multiple protective effects, including increasing the expression of CuZn-SOD and other undefined mechanisms.

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-{kappa}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{alpha}, PPARß/{delta}, and PPAR{gamma}) 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{gamma} is now known to be expressed in both endothelium and vascular muscle. Activation of PPAR{gamma} reduces the secretion of endothelin, decreases activation of nuclear factor-{kappa}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{gamma} increase levels of CuZn-SOD in cultured endothelium,30 suggesting one additional mechanism by which PPAR{gamma} may exert protective effects within the vasculature (Figure).

Based on these characteristics, it was hypothesized that expression of PPAR{gamma} 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{gamma} agonists improved endothelial function. Importantly, some of these initial findings suggest that beneficial effects may occur by actions of PPAR{gamma} within the vessel wall.32 Thus, it will be of interest in future studies to define the physiological role of PPAR{gamma} in the carotid artery and cerebral circulation and to determine how impairment of PPAR{gamma} 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.

References

  1. Mori T, Nagata K, Town T, Tan J, Matsui T, Asano T. Intracisternal increase of superoxide anion production in a canine subarachnoid hemorrhage model. Stroke. 2001; 32: 636–642.[Abstract/Free Full Text]
  2. Lentz SR, Dayal S, Arning E, Bottiglieri T Sigmund CD Faraci FM. Role of superoxide in cerebral vascular dysfunction in hyperhomocysteinemic mice. Circulation. 2002; 106: II-111.Abstract.
  3. Gunnett CA, Heistad DD, Faraci FM. Interleukin-10 protects endothelium-dependent relaxation during diabetes: role of superoxide. Diabetes. 2002; 51: 1931–1937.[Abstract/Free Full Text]
  4. Didion SP, Faraci FM. Angiotensin II produces superoxide-mediated impairment of endothelial function in cerebral arterioles. Stroke. Abstract. In press.
  5. Sun H, Mayhan WG. Temporal effect of alcohol consumption on reactivity of pial arterioles: role of oxygen radicals. Am J Physiol. 2001; 280: H992–H1001.
  6. Chan PH. Reactive oxygen radicals in signaling and damage in the ischemic brain. J Cerebral Blood Flow Metab. 2001; 21: 2–14.[CrossRef][Medline] [Order article via Infotrieve]
  7. Fukai T, Siegfried MR, Ushio-Fukai M, Cheng Y, Kojda G, Harrison DG. Regulation of the vascular extracellular superoxide dismutase by nitric oxide and exercise training. J Clin Invest. 2000; 105: 1631–1639.[Medline] [Order article via Infotrieve]
  8. Didion SP, Ryan MJ, Didion LA, Fegan PE, Sigmund CD, Faraci FM. Increased superoxide and vascular dysfunction in CuZnSOD-deficient mice. Circ Res. 2002; 91: 938–944.[Abstract/Free Full Text]
  9. Stalin P, Kurlsson K, Johansson BO, Marklund SL. The interstitium of the human arterial wall contains very large amounts of extracellular superoxide dismutase. Arterioscler Thromb Vasc Biol. 1995; 15: 2032–2036.[Abstract/Free Full Text]
  10. Didion SP, Hathaway CA, Faraci FM. Superoxide levels and function of cerebral blood vessels following inhibition of CuZn-SOD. Am J Physiol. 2001; 281: H1697–H1703.
  11. Baumbach GL, Didion SP, Faraci FM. Deficiency of copper-zinc superoxide dismutase promotes cerebral vascular hypertrophy. FASEB J. Abstract. In press.
  12. Didion SP, FMFaraci. Overexpression of CuZn-SOD protects against ceramide-induced endothelial dysfunction. FASEB J. 2002; 16: A1136.Abstract.
  13. Kim CD, Shin HK, Lee HS, Lee JH, Lee TH, Hong KW. Gene transfer of Cu/Zn SOD to cerebral vessels prevents FPI-induced CBF autoregulatory dysfunction. Am J Physiol Heart Circ Physiol. 2002; 282: H1836–H1842.[Abstract/Free Full Text]
  14. Suzuki K, Tatsumi H, Satoh S, Senda T, Nakata T, Fujii J, Taniguchi N. Manganese-superoxide dismutase in endothelial cells: localization and mechanism of induction. Am J Physiol. 1993; 265: H1173–1178.[Medline] [Order article via Infotrieve]
  15. Napoli C, Witztum JL, de Nigris F, Palumbo G, D’Armiento FP, Palinski W. Intracranial arteries of human fetuses are more resistant to hypercholesterolemia-induced fatty streak formation than extracranial arteries. Circulation. 1999; 99: 2003–2010.[Abstract/Free Full Text]
  16. Oldendorf WH, Cornfield ME, Brown WJ. The large apparent work capability of the blood-brain barrier: a study of the mitochondrial content of capillary endothelial cells in brain and other tissues of the rat. Ann Neurol. 1977; 1: 409–417.[CrossRef][Medline] [Order article via Infotrieve]
  17. Ballinger SW, Patterson C, Knight-Lozano CA, Burow DL, Conklin CA, Hu Z, Reuf J, Horaist C, Lebovitz R, Hunter GC, McIntyre K, Runge MS. Mitochondrial integrity and function in atherogenesis. Circulation. 2002; 106: 544–549.[Abstract/Free Full Text]
  18. Ruetzler CA, Furuya K, Takeda H, Hallenbeck JM. Brain vessels normally undergo cyclic activation and inactivation: evidence from tumor necrosis factor-{alpha}, heme oxygenase-1, and manganese superoxide dismutase immunostaining of vessels and perivascular brain cells. J Cerebral Blood Flow Metab. 2001; 21: 244–252.[CrossRef][Medline] [Order article via Infotrieve]
  19. Schaper M, Gergely S, Lykkesfeldt J, Zbaren J, Leib SL, Tauber MG, Christen S. Cerebral vasculature in the major target of oxidative protein alterations in bacterial meningitis. J Neuropath Exp Neurol. 2002; 61: 605–613.[Medline] [Order article via Infotrieve]
  20. Demchenko IT, Oury TD, Crapo JD, Piantadosi CA. Regulation of the brain’s vascular responses to oxygen. Circ Res. 2002; 91: 1031–1037.[Abstract/Free Full Text]
  21. McGirt MJ, Parra A, Sheng H, Higuchi Y, Oury TD, Laskowitz DT, Pearlstein RD, Warner DS. Attenuation of cerebral vasospasm after subarachnoid hemorrhage in mice overexpressing extracellular superoxide dismutase. Stroke. 2002; 33: 2317–2323.[Abstract/Free Full Text]
  22. Watanabe Y, Chu Y, Andresen JJ, Nakane H, Faraci FM, Heistad DD. Gene transfer of extracellular superoxide dismutase reduces vasospasm after subarachnoid hemorrhage. Stroke. 2003; 34: 434–440.[Abstract/Free Full Text]
  23. Faraci FM, Heistad DD. Regulation of the cerebral circulation: role of endothelium and potassium channels. Physiol Rev. 1998; 78: 53–97.[Abstract/Free Full Text]
  24. Buchwalow IB, Podzuweit T, Bocker W, Samoilova VE, Thomas S, Wellner M, Baba HA, Robenek H, Schnekenburger J, Lerch MM. Vascular smooth muscle and nitric oxide synthase. FASEB J. 2002; 16: 500–508.[Abstract/Free Full Text]
  25. Lamping KG, Faraci FM. Role of sex differences and effects of endothelial NO synthase deficiency in responses of carotid arteries to serotonin. Arterioscler Thromb Vasc Biol. 2001; 21: 523–528.[Abstract/Free Full Text]
  26. McGirt MJ, Lynch JR, Parra A, Sheng H, Pearlstein RD, Laskowitz DT, Pelligrino DA, Warner DS. Simvastatin increases endothelial nitric oxide synthase and ameliorates cerebral vasospasm resulting from subarachnoid hemorrhage. Stroke. 2002; 33: 2950–2956.[Abstract/Free Full Text]
  27. Limbourg FP, Huang Z, Plumier J-C, Simoncini T, Fujioka M, Tuckermann J, Schütz G, Moskowitz MA, Liao JK. Rapid nontranscriptional activation of endothelial nitric oxide synthase mediates increased cerebral blood flow and stroke protection by corticosteroids. J Clin Invest. 2002; 110: 1729–1738.[CrossRef][Medline] [Order article via Infotrieve]
  28. Buchan KW, Hassall DG. PPAR agonists as direct modulators of the vessel wall in cardiovascular disease. Med Res Rev. 2000; 20: 350–366.[CrossRef][Medline] [Order article via Infotrieve]
  29. Tedgui A, Mallat Z. Anti-inflammatory mechanisms in the vascular wall. Circ Res. 2001; 88: 877–887.[Abstract/Free Full Text]
  30. Inoue I, Goto S, Matsunaga T, Nakajima T, Awata T, Hokari S, Komoda T, Katayama S. The ligands/activators for peroxisome proliferator-activated receptor {alpha} (PPAR{alpha}) and PPAR{gamma} increase Cu2+, Zn2+-superoxide dismutase and decrease p22phox message expressions in primary endothelial cells. Metabolism. 2001; 50: 3–11.[CrossRef][Medline] [Order article via Infotrieve]
  31. Didion SP, MJRyan, Faraci FM, Sigmund CD. Activation of PPAR{gamma} reduces blood pressure and improves vascular function in hypertensive transgenic mice. FASEB J. 2002; 16: A81.
  32. Didion SP, Ryan MJ, Sigmund CD, Faraci FM. PPAR{gamma} activation improves endothelial function in type II diabetes. FASEB J. Abstract. In press.



This article has been cited by other articles:


Home page
 StrokeHome page
S. C. Fagan, D. C. Hess, E. J. Hohnadel, D. M. Pollock, and A. Ergul
Targets for Vascular Protection After Acute Ischemic Stroke
Stroke, September 1, 2004; 35(9): 2220 - 2225.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Faraci, F. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Faraci, F. M.

Stroke Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search
Copyright © 2003 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited.