doi: 10.1161/01.RES.0000250961.47984.80
© 2006 American Heart Association, Inc.
Editorials |
Protecting the Brain With eNOS
Run for Your Life
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
See related article, pages 1132–1140
Key Words: endothelium • nitric oxide • cerebral circulation • exercise
Nitric oxide (NO) plays a major role in both vascular and neural biology in health and disease. This concept is exemplified when one examines the role of NO in the brain and the cerebral circulation. NO is a potent vasodilator, and blood vessels in the brain are normally exposed to NO from 2 major sources—endothelium and neurons. Acting as a messenger molecule, NO mediates the majority of endothelium-dependent responses in the brain.1 The source of this NO is the endothelial isoform of NO synthase (eNOS). This prominent role for NO has been observed in a variety of blood vessels from multiple species including humans.1–3 Through this signaling mechanism, NO influences resting vascular tone and mediates responses to varied stimuli, including endothelium-dependent agonists and increases in blood flow (Figure).1,4,5 In addition, eNOS inhibits vasoconstrictor responses and cerebral vasospasm6–8 and can affect permeability of cerebral endothelium, the blood-brain barrier (Figure).9 eNOS normally inhibits cerebral vascular growth or hypertrophy (Figure),10 a structural change that can have functional consequences by impairing of maximal vasodilator capacity. Impairment of NO-mediated signaling is a key underlying mechanism of vascular dysfunction in diverse forms of disease and aging.1,11–13 Impairment of these eNOS-dependent mechanisms in the presence of cardiovascular risk factors may contribute to reductions in cerebral blood flow, vascular cognitive impairment, and stroke.12,14
|
Among the more interesting recent findings with regard to eNOS are those related to the impact of the enzyme on neuronal function. For example, basal NO produced by eNOS in endothelium affects local neuronal transmission via its effects on axons (Figure).15 Neuronal stem cells are present in portions of the brain and the activation of these cells by injury (ie, ischemia) can result in neurogenesis that promotes functional recovery.16 Endothelial cells promote neurogenesis.17,18 eNOS deficient mice have impaired angiogenesis as well as impaired neurogenesis and recovery of neuronal functional following experimental stroke.18 Thus, endothelial dysfunction and loss of eNOS-mediated signaling produces deleterious vascular effects, but may also impair neuronal signaling and neurogenesis following stroke (Figure).
Previous studies have demonstrated that eNOS protects against brain injury following focal ischemia, in part by contributing to the maintenance of greater levels of blood flow.19 Exercise increases vascular expression of eNOS, improves endothelium-dependent relaxation, and increases cerebral blood flow.19,20 The study by Gertz et al21 in this issue of Circulation Research sought to extend those findings, provide additional mechanistic insight into how eNOS and exercise produce such beneficial effects, and to examine the impact of eNOS on long-term recovery from ischemia. The approach that was used was the study of mice which exercised voluntarily (by running on a wheel) compared with sedentary mice. Using this design, mice that exercised had reduced infarct size following transient occlusion of one middle cerebral artery compared with controls. This effect was dependent on NO and eNOS, as the protection was prevented by pharmacological inhibition of NOS and was absent in eNOS-deficient animals. Exercise also increased long-term cognitive function following stroke.
Endothelial progenitor cells (EPCs) are known to increase endothelial function and angiogenesis, and exercise increases EPC numbers in blood and bone marrow as well as stimulate the formation of new blood vessels.22 In this new study,21 exercise increased the circulating levels of vascular endothelial growth factor, which activates eNOS and promotes angiogenesis, along with eNOS expression in the vasculature and in EPCs. Recruitment of EPCs occurred in the ischemic region and exercise augmented this effect. Exercise increased vascular density and cerebral blood flow in ischemic and nonischemic brain regions. Thus, exercise produced both short and long-term effects that increased cerebral perfusion and cognitive function through its effects on eNOS and EPCs (Figure).
Many questions arise from this work. What is the relative role of increased expression of eNOS within endothelial cells versus within EPCs? Would exercise produce similar protective effects in aged animals or in models with cardiovascular risk factors such as hypertension? Such risk factors produce endothelial dysfunction in the brain which is thought to contribute to an increased likelihood of stroke and/or cognitive decline.1,12 How does exercise produce these effects, including increasing the expression of eNOS? Clearly one potential mechanism relates to effects of increased shear stress on expression of the eNOS gene in endothelium. However, although cerebral blood flow may increase in regions involved with locomotion, global cerebral blood flow changes little during exercise.23,24 Are only the regions which exhibit increased cerebral blood flow during exercise the sites that exhibit increased eNOS expression and neuroprotection following ischemia? Are other regions protected? Do mechanisms other than increases in shear stress increase expression of eNOS?
A concept that is sometimes put forward is that the functional importance of eNOS and NO-mediated signaling decreases with progression from aorta and large arteries down the vascular tree into the microcirculation. This simple view is not accurate for the brain. There are many examples in which endothelium-derived NO and eNOS have a major impact at the level of the cerebral microcirculation—including in arterioles within the brain parenchyma—now often referred to as the neurovascular unit.1,3,4,10,15,18 Many of the eNOS dependent effects described in the study by Gertz et al21 occurred in the microcirculation within the brain parenchyma.
The findings described above provide yet another example of the potential translational benefits from targeting eNOS with therapeutic approaches. Previous studies suggest that such targeting may be achieved using pharmacological approaches with agents such as statins, corticosteroids, or thyroid hormone.25–27 Increases in cerebral blood flow occur in response to all of these agents and these increases are mediated in large part by eNOS.25–27 Alternatively, increased expression of eNOS can be achieved using approaches such as gene transfer.28 These recent studies highlight the potential value of a much simpler approach, that of voluntary exercise.
 |
Acknowledgments |
|---|
Sources of Funding
Work reviewed in this manuscript from this laboratory was supported by National Institutes of Health grants HL-38901, NS-24621, and HL-62984; and by a Bugher Foundation Award in Stroke from the American Heart Association (0575092N).
Disclosures
None.
|
Footnotes |
|---|
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
|
References |
|---|
 Top References |
|---|
1. Faraci FM, Heistad DD. Regulation of the cerebral circulation: role of endothelium and potassium channels. Physiol Rev. 1998; 78: 53–97.
2. Faraci FM. Role of nitric oxide in regulation of basilar artery tone in vivo. Am J Physiol. 1990; 259: H1216–H1221.[Medline] [Order article via Infotrieve]
3. Elhusseiny A, Hamel E. Muscarinic - but not nicotinic - acetylcholine receptors mediate a nitric oxide-dependent dilation in brain cortical arterioles: a possible role for the M5 receptor subtype. J Cereb Blood Flow Metabol. 2000; 20: 298–305.[CrossRef][Medline] [Order article via Infotrieve]
4. Ngai AC, Winn HR. Modulation of cerebral arteriolar diameter by intraluminal flow and pressure. Circulation Res. 1995; 77: 832–840.
5. Paravicini TM, Miller AA, Drummond GR, Sobey CG. Flow-induced cerebral vasodilatation in vivo involves activation of phosphatidylinositol-3 kinase, NADPH-oxidase, and nitric oxide synthase. J Cereb Blood Flow Metabol. 2006; 26: 836–845.[CrossRef][Medline] [Order article via Infotrieve]
6. 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.
7. Santhanam AV, Smith LA, Akiyama M, Rosales AG, Bailey KR, Katusic ZS. Role of endothelial NO synthase phosphorylation in cerebrovascular protective effect of recombinant erythropoietin during subarachnoid hemorrhage-induced cerebral vasospasm. Stroke. 2005; 36: 2731–2737.
8. 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.
9. Koedel U, Paul R, Winkler F, Kastenbauer S, Huang PL, Pfister HW. Lack of endothelial nitric oxide synthase aggravates murine pneumococcal meningitis. J Neuropathol Exp Neurol. 2001; 60: 1041–1050.[Medline] [Order article via Infotrieve]
10. Baumbach GL, Sigmund CD, Faraci FM. Structure of cerebral arterioles in mice deficient in expression of the gene for endothelial nitric oxide synthase. Circulation Res. 2004; 95: 822–829.
11. Girouard H, Iadecola C. Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer disease. J Appl Physiol. 2006; 100: 328–335.
12. Faraci FM. Oxidative stress: the curse that underlies cerebral vascular dysfunction? Stroke. 2005; 36: 186–188.
13. Feletou M, Vanhoutte PM. Endothelial dysfunction: a multifaceted disorder. Am J Physiol. 2006; 291: H985–H1002.[CrossRef]
14. Iadecola C. Atherosclerosis and neurodegeneration: unexpected conspirators in Alzheimer’s dementia. Arterioscler Thromb Vasc Biol. 2003; 23: 1951–1953.
15. Garthwaite G, Bartus K, Malcolm D, Goodwin D, Kollb-Sielecka M, Dooldeniya C, Garthwaite J. Signaling from blood vessels to CNS axons through nitric oxide. J Neurosci. 2006; 26: 7730–7740.
16. Bernal GM, Peterson DA. Neural stem cells as therapeutic agents for age-related brain repair. Aging Cell. 2004; 3: 345–351.[CrossRef][Medline] [Order article via Infotrieve]
17. Shen Q, Goderie SK, Jin L, Karanth N, Sun Y, Abramova N, Vincent P, Pumiglia K, Temple S. Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science. 2004; 304: 1338–1340.
18. Chen J, Zacharek A, Zhang C, Jiang H, Li Y, Roberts C, Lu M, Kapke A, Chopp M. Endothelial nitric oxide synthase regulates brain-derived neurotrophic factor expression and neurogenesis after stroke in mice. J Neurosci. 2005; 25: 2366–2375.
19. Endres M, Laufs U, Liao JK, Moskowitz MA. Targeting eNOS for stroke protection. Trends Neurosci. 2004; 27: 283–289.[CrossRef][Medline] [Order article via Infotrieve]
20. Endres M, Gertz K, Lindauer U, Katchanov J, Schultze J, Schrock H, Nickenig G, Kuschinsky W, Dirnagl U, Laufs U. Mechanisms of stroke protection by physical activity. Ann Neurol. 2003; 54: 582–590.[CrossRef][Medline] [Order article via Infotrieve]
21. Gertz K, Priller J, Kronenberg G, Fink KB, Winter B, Schroeck H, Ji S, Milosevic M, Harms C, Boehm M, Dirnagl U, Laufs U, Endres M. Physical activity improves long-term stroke outcome via eNOS-depdendent augmentation of neo-vascularization and cerebral blood flow. Circ Res. 2006; 99: 1132–1140.
22. Laufs U, Werner N, Link A, Endres M, Wassmann S, Jürgens K, Miche E, Böhm M, Nickenig G. Physical training increases endothelial progenitor cells, inhibits neointima formation, and enhances angiogenesis. Circulation. 2004; 109: 220–226.
23. Gross PM, Marcus ML, Heistad DD. Regional distribution of cerebral blood flow during exercise in dogs. J Appl Physiol. 1980; 48: 213–217.
24. Hohimer AR, Hales JR, Rowell LB, Smith OA. Regional distribution of blood flow during mild dynamic leg exercise in the baboon. J Appl Physiol. 1983; 55: 1173–1177.
25. Hiroi Y, Kim HH, Ying H, Furuya F, Huang Z, Simoncini T, Noma K, Ueki K, Nguyen NH, Scanlan TS, Moskowitz MA, Cheng SY, Liao JK. Rapid nongenomic actions of thyroid hormone. Proc Natl Acad Sci. 2006; 103: 14104–14109.
26. Limbourg FP, Huang Z, Plumier JC, Simoncini T, Fujioka M, Tuckermann J, Schutz 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]
27. Endres M, Laufs U, Huang Z, Nakamura T, Huang P, Moskowitz MA, Liao JK. Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase. Proc Natl Acad Sci. 1998; 95: 8880–8885.
28. Khurana VG, Smith LA, Baker TA, Eguchi D, O’Brien T, Katusic ZS. Protective vasomotor effects of in vivo recombinant endothelial nitric oxide synthase gene expression in a canine model of cerebral vasospasm. Stroke. 2002; 33: 782–789.
Related Article:
Circ. Res. 2006 99: 1132-1140.
This article has been cited by other articles:
 |
|
 |
|
  T. Nakamura, E. Yamamoto, K. Kataoka, T. Yamashita, Y. Tokutomi, Y.-F. Dong, S. Matsuba, H. Ogawa, and S. Kim-Mitsuyama Pioglitazone Exerts Protective Effects Against Stroke in Stroke-Prone Spontaneously Hypertensive Rats, Independently of Blood Pressure Stroke, November 1, 2007; 38(11): 3016 - 3022. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||