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Reactive Oxygen Species and the Regulation of Cerebral Vascular Tone

  • T. Michael De Silva
  • Frank M. FaraciEmail author
Chapter
Part of the Oxidative Stress in Applied Basic Research and Clinical Practice book series (OXISTRESS)

Abstract

This chapter summarizes concepts related to the effects of reactive oxygen species and oxidative stress on vascular tone in the cerebral circulation. The impact of different reactive oxygen species as well as enzymatic sources of these molecules (particularly NADPH oxidase) is outlined along with endogenous mechanisms that protect against oxidative stress. Direct effects of reactive oxygen species on vascular tone are described. In addition, an overview is presented regarding effects of these molecules on key adaptive responses. The majority of this work has been performed in models of disease. Although reactive oxygen species may be produced at low levels in normal healthy blood vessels, they appear to exert little influence on vascular tone under those conditions. For both endothelium-dependent vasodilation and neurovascular coupling, reactive oxygen species do not affect responses normally but have substantial effects in disease and with aging. In contrast, the importance of reactive oxygen species in relation to autoregulation and chemoregulation (cerebrovascular responses to carbon dioxide and oxygen) has only been studied to a limited extent with somewhat inconsistent results. Overall, reactive oxygen species have substantial effects on vascular tone in brain, particularly in models of cerebrovascular disease.

Keywords

Endothelial function Myogenic tone Autoregulation Cerebral blood flow Oxidative stress NAPDH oxidase Neurovascular coupling 

Notes

Acknowledgement

Work summarized in this chapter was supported by research grants from the National Institute of Health (NS-096465, NS-24621, HL-62984, and HL-113863), the Department of Veteran’s Affair’s (BX001399), and the Fondation Leducq (Transatlantic Network of Excellence on the Pathogenesis of Cerebral Small Vessel Disease). TMD was the recipient of an Overseas Post-doctoral Fellowship from the National Health and Medical Research Council of Australia (1053786).

References

  1. 1.
    Faraci FM, Didion SP. Vascular protection: superoxide dismutase isoforms in the vessel wall. Arterioscler Thromb Vasc Biol. 2004;24:1367–73.PubMedCrossRefGoogle Scholar
  2. 2.
    Faraci FM. Protecting against vascular disease in brain. Am J Physiol. 2011;300:H1566–82.Google Scholar
  3. 3.
    Miller AA, Drummond GR, Schmidt HH, Sobey CG. NADPH oxidase activity and function are profoundly greater in cerebral versus systemic arteries. Circ Res. 2005;97:1055–62.PubMedCrossRefGoogle Scholar
  4. 4.
    Miller AA, Drummond GR, De Silva TM, Mast AE, Hickey H, Williams JP, et al. NADPH oxidase activity is higher in cerebral versus systemic arteries of four animal species: role of Nox2. Am J Physiol. 2009;296:H220–5.Google Scholar
  5. 5.
    Chan SL, Baumbach GL. Deficiency of Nox2 prevents angiotensin II-induced inward remodeling in cerebral arterioles. Front Physiol. 2013;4:133.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Chan SL, Baumbach GL. Nox2 deficiency prevents hypertension-induced vascular dysfunction and hypertrophy in cerebral arterioles. Int J Hypertens. 2013;2013:793630.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Baumbach GL, Didion SP, Faraci FM. Hypertrophy of cerebral arterioles in mice deficient in expression of the gene for CuZn superoxide dismutase. Stroke. 2006;37:1850–5.PubMedCrossRefGoogle Scholar
  8. 8.
    Starke RM, Chalouhi N, Ali MS, Jabbour PM, Tjoumakaris SI, Gonzalez LF, et al. The role of oxidative stress in cerebral aneurysm formation and rupture. Curr Neurovasc Res. 2013;10:247–55.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Wood KC, Hebbel RP, Granger DN. Endothelial cell NADPH oxidase mediates the cerebral microvascular dysfunction in sickle cell transgenic mice. FASEB J. 2005;19:989–91.PubMedGoogle Scholar
  10. 10.
    Freeman LR, Keller JN. Oxidative stress and cerebral endothelial cells: regulation of the blood-brain-barrier and antioxidant based interventions. Biochim Biophys Acta. 1822;2012:822–9.Google Scholar
  11. 11.
    Drummond GR, Sobey CG. Endothelial NADPH oxidases: which NOX to target in vascular disease? Trends Endo Metab. 2014;25:452–63.CrossRefGoogle Scholar
  12. 12.
    Leopold JA, Loscalzo J. Oxidative risk for atherothrombotic cardiovascular disease. Free Radic Biol Med. 2009;47:1673–706.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Oldendorf WH, Cornford 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;1:409–17.PubMedCrossRefGoogle Scholar
  14. 14.
    Busija DW, Katakam PV. Mitochondrial mechanisms in cerebral vascular control: shared signaling pathways with preconditioning. J Vasc Res. 2014;51:175–89.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Didion S, Hathaway C, Faraci F. Superoxide levels and function of cerebral blood vessels after inhibition of CuZn-SOD. Am J Physiol. 2001;281:H1697–703.Google Scholar
  16. 16.
    Kontos HA, Wei EP, Kukreja RC, Ellis EF, Hess ML. Differences in endothelium-dependent cerebral dilation by bradykinin and acetylcholine. Am J Physiol. 1990;258:H1261–6.PubMedGoogle Scholar
  17. 17.
    Kontos HA, Wei EP, Povlishock JT, Christman CW. Oxygen radicals mediate the cerebral arteriolar dilation from arachidonate and bradykinin in cats. Circ Res. 1984;55:295–303.PubMedCrossRefGoogle Scholar
  18. 18.
    Chrissobolis S, Banfi B, Sobey CG, Faraci FM. Role of Nox isoforms in angiotensin II-induced oxidative stress and endothelial dysfunction in brain. J Appl Physiol. 2012;113:184–91.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Chrissobolis S, Faraci FM. The role of oxidative stress and NADPH oxidase in cerebrovascular disease. Trends Mol Med. 2008;14:495–502.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Montezano AC, Burger D, Ceravolo GS, Yusuf H, Montero M, Touyz RM. Novel Nox homologues in the vasculature: focusing on Nox4 and Nox5. Clin Sci. 2011;120:131–41.PubMedCrossRefGoogle Scholar
  21. 21.
    Santhanam AV, d'Uscio LV, Katusic ZS. Erythropoietin increases bioavailability of tetrahydrobiopterin and protects cerebral microvasculature against oxidative stress induced by eNOS uncoupling. J Neurochem. 2014;131:521–9.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Santhanam AV, d'Uscio LV, Smith LA, Katusic ZS. Uncoupling of eNOS causes superoxide anion production and impairs NO signaling in the cerebral microvessels of hph-1 mice. J Neurochem. 2012;122:1211–8.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Wei EP, Kontos HA, Beckman JS. Mechanisms of cerebral vasodilation by superoxide, hydrogen peroxide, and peroxynitrite. Am J Physiol. 1996;271:H1262–6.PubMedGoogle Scholar
  24. 24.
    Didion SP, Faraci FM. Effects of NADH and NADPH on superoxide levels and cerebral vascular tone. Am J Physiol. 2002;282:H688–95.Google Scholar
  25. 25.
    Park L, Anrather J, Zhou P, Frys K, Wang G, Iadecola C. Exogenous NADPH increases cerebral blood flow through NADPH oxidase-dependent and -independent mechanisms. Arterioscler Thromb Vasc Biol. 2004;24:1860–5.PubMedCrossRefGoogle Scholar
  26. 26.
    Miller AA, Drummond GR, Sobey CG. Novel isoforms of NADPH-oxidase in cerebral vascular control. Pharmacol Ther. 2006;111:928–48.PubMedCrossRefGoogle Scholar
  27. 27.
    Cosentino F, Sill JC, Katusic ZS. Role of superoxide anions in the mediation of endothelium-dependent contractions. Hypertension. 1994;23:229–35.PubMedCrossRefGoogle Scholar
  28. 28.
    Amberg GC, Earley S, Glapa SA. Local regulation of arterial L-type calcium channels by reactive oxygen species. Circ Res. 2010;107:1002–10.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Faraci FM. Reactive oxygen species: influence on cerebral vascular tone. J Appl Physiol. 2006;100:739–43.PubMedCrossRefGoogle Scholar
  30. 30.
    Sobey CG, Heistad DD, Faraci FM. Mechanisms of bradykinin-induced cerebral vasodilatation in rats. Evidence that reactive oxygen species activate K+ channels. Stroke. 1997;28:2290–4.PubMedCrossRefGoogle Scholar
  31. 31.
    Faraci FM, Heistad DD. Regulation of the cerebral circulation: role of endothelium and potassium channels. Physiol Rev. 1998;78:53–97.PubMedGoogle Scholar
  32. 32.
    Faraci FM, Sobey CG. Role of potassium channels in regulation of cerebral vascular tone. J Cereb blood Flow Metabl. 1998;18:1047–63.CrossRefGoogle Scholar
  33. 33.
    Faraci FM. Hydrogen peroxide: watery fuel for change in vascular biology. Arterioscler Thromb Vasc Biol. 2006;26:1931–3.PubMedCrossRefGoogle Scholar
  34. 34.
    Brzezinska AK, Gebremedhin D, Chilian WM, Kalyanaraman B, Elliott SJ. Peroxynitrite reversibly inhibits Ca2+-activated K+ channels in rat cerebral artery smooth muscle cells. Am J Physiol. 2000;278:H1883–90.Google Scholar
  35. 35.
    Elliott SJ, Lacey DJ, Chilian WM, Brzezinska AK. Peroxynitrite is a contractile agonist of cerebral artery smooth muscle cells. Am J Physiol. 1998;275:H1585–91.PubMedGoogle Scholar
  36. 36.
    Girouard H, Park L, Anrather J, Zhou P, Iadecola C. Cerebrovascular nitrosative stress mediates neurovascular and endothelial dysfunction induced by angiotensin II. Arterioscler Thromb Vasc Biol. 2007;27:303–9.PubMedCrossRefGoogle Scholar
  37. 37.
    Maneen MJ, Cipolla MJ. Peroxynitrite diminishes myogenic tone in cerebral arteries: role of nitrotyrosine and F-actin. Am J Physiol. 2007;292:H1042–50.Google Scholar
  38. 38.
    Modrick ML, Didion SP, Sigmund CD, Faraci FM. Role of oxidative stress and AT1 receptors in cerebral vascular dysfunction with aging. Am J Physiol. 2009;296:H1914–9.Google Scholar
  39. 39.
    Didion SP, Kinzenbaw DA, Schrader LI, Faraci FM. Heterozygous CuZn superoxide dismutase deficiency produces a vascular phenotype with aging. Hypertension. 2006;48:1072–9.PubMedCrossRefGoogle Scholar
  40. 40.
    Park L, Wang G, Moore J, Girouard H, Zhou P, Anrather J, et al. The key role of transient receptor potential melastatin-2 channels in amyloid-beta-induced neurovascular dysfunction. Nat Comm. 2014;5:5318.CrossRefGoogle Scholar
  41. 41.
    Bauer J, Ripperger A, Frantz S, Ergun S, Schwedhelm E, Benndorf RA. Pathophysiology of isoprostanes in the cardiovascular system: implications of isoprostane-mediated thromboxane A2 receptor activation. Br J Pharmacol. 2014;171:3115–31.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Katusic ZS, Austin SA. Endothelial nitric oxide: protector of a healthy mind. Eur Heart J. 2014;35:888–94.PubMedCrossRefGoogle Scholar
  43. 43.
    Green DJ, Dawson EA, Groenewoud HM, Jones H, Thijssen DH. Is flow-mediated dilation nitric oxide mediated? A meta-analysis. Hypertension. 2014;63:376–82.PubMedCrossRefGoogle Scholar
  44. 44.
    Lind L, Berglund L, Larsson A, Sundstrom J. Endothelial function in resistance and conduit arteries and 5-year risk of cardiovascular disease. Circulation. 2011;123:1545–51.PubMedCrossRefGoogle Scholar
  45. 45.
    Flammer AJ, Luscher TF. Three decades of endothelium research: from the detection of nitric oxide to the everyday implementation of endothelial function measurements in cardiovascular diseases. Swiss Med Wkly. 2010;140:w13122.PubMedGoogle Scholar
  46. 46.
    Volpe M, Iaccarino G, Vecchione C, Rizzoni D, Russo R, Rubattu S, et al. Association and cosegregation of stroke with impaired endothelium-dependent vasorelaxation in stroke prone, spontaneously hypertensive rats. J Clin Invest. 1996;98:256–61.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Hill-Eubanks DC, Gonzales AL, Sonkusare SK, Nelson MT. Vascular TRP channels: performing under pressure and going with the flow. Physiology. 2014;29:343–60.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Kamouchi M, Ago T, Kitazono T. Brain pericytes: emerging concepts and functional roles in brain homeostasis. Cell Mol Neurobiol. 2011;31:175–93.PubMedCrossRefGoogle Scholar
  49. 49.
    Armulik A, Genove G, Betsholtz C. Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev Cell. 2011;21:193–215.PubMedCrossRefGoogle Scholar
  50. 50.
    Hall CN, Reynell C, Gesslein B, Hamilton NB, Mishra A, Sutherland BA, et al. Capillary pericytes regulate cerebral blood flow in health and disease. Nature. 2014;508:55–60.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    De Silva TM, Modrick ML, Ketsawatsomkron P, Lynch C, Chu Y, Pelham CJ, et al. Role of peroxisome proliferator-activated receptor-gamma in vascular muscle in the cerebral circulation. Hypertension. 2014;64:1088–93.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Francis SH, Busch JL, Corbin JD, Sibley D. cGMP-dependent protein kinases and cGMP phosphodiesterases in nitric oxide and cGMP action. Pharmacol Rev. 2010;62:525–63.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Sobey CG, Faraci FM. Effects of a novel inhibitor of guanylyl cyclase on dilator responses of mouse cerebral arterioles. Stroke. 1997;28:837–42.PubMedCrossRefGoogle Scholar
  54. 54.
    Katakam PV, Domoki F, Lenti L, Gaspar T, Institoris A, Snipes JA, et al. Cerebrovascular responses to insulin in rats. J Cereb Blood Flow Metab. 2009;29:1955–67.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Chrissobolis S, Drummond GR, Faraci FM, Sobey CG. Chronic aldosterone administration causes Nox2-mediated increases in reactive oxygen species production and endothelial dysfunction in the cerebral circulation. J Hypertens. 2014;32:1815–21.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    De Silva TM, Brait VH, Drummond GR, Sobey CG, Miller AA. Nox2 oxidase activity accounts for the oxidative stress and vasomotor dysfunction in mouse cerebral arteries following ischemic stroke. PLoS One. 2011;6, e28393.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Girouard H, Park L, Anrather J, Zhou P, Iadecola C. Angiotensin II attenuates endothelium-dependent responses in the cerebral microcirculation through Nox-2-derived radicals. Arterioscler Thromb Vasc Biol. 2006;26:826–32.PubMedCrossRefGoogle Scholar
  58. 58.
    Kazama K, Anrather J, Zhou P, Girouard H, Frys K, Milner TA, et al. Angiotensin II impairs neurovascular coupling in neocortex through NADPH oxidase-derived radicals. Circ Res. 2004;95:1019–26.PubMedCrossRefGoogle Scholar
  59. 59.
    Lynch CM, Kinzenbaw DA, Chen X, Zhan S, Mezzetti E, Filosa J, et al. Nox2-derived superoxide contributes to cerebral vascular dysfunction in diet-induced obesity. Stroke. 2013;44:3195–201.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Park L, Anrather J, Girouard H, Zhou P, Iadecola C. Nox2-derived reactive oxygen species mediate neurovascular dysregulation in the aging mouse brain. J Cereb Blood Flow Metab. 2007;27:1908–18.PubMedCrossRefGoogle Scholar
  61. 61.
    Park L, Anrather J, Zhou P, Frys K, Pitstick R, Younkin S, et al. NADPH-oxidase-derived reactive oxygen species mediate the cerebrovascular dysfunction induced by the amyloid beta peptide. J Neurosci. 2005;25:1769–77.PubMedCrossRefGoogle Scholar
  62. 62.
    Park L, Zhou P, Pitstick R, Capone C, Anrather J, Norris EH, et al. Nox2-derived radicals contribute to neurovascular and behavioral dysfunction in mice overexpressing the amyloid precursor protein. Proc Natl Acad Sci. 2008;105:1347–52.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Walker AE, Henson GD, Reihl KD, Nielson EI, Morgan RG, Lesniewski LA, et al. Beneficial effects of lifelong caloric restriction on endothelial function are greater in conduit arteries compared to cerebral resistance arteries. Age. 2014;36:559–69.PubMedCrossRefGoogle Scholar
  64. 64.
    Nicolakakis N, Aboulkassim T, Ongali B, Lecrux C, Fernandes P, Rosa-Neto P, et al. Complete rescue of cerebrovascular function in aged Alzheimer's disease transgenic mice by antioxidants and pioglitazone, a peroxisome proliferator-activated receptor gamma agonist. J Neurosci. 2008;28:9287–96.PubMedCrossRefGoogle Scholar
  65. 65.
    Tong XK, Lecrux C, Rosa-Neto P, Hamel E. Age-dependent rescue by simvastatin of Alzheimer's disease cerebrovascular and memory deficits. J Neurosci. 2012;32:4705–15.PubMedCrossRefGoogle Scholar
  66. 66.
    Wardlaw JM, Smith C, Dichgans M. Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging. Lancet Neurol. 2013;12:483–97.PubMedCrossRefGoogle Scholar
  67. 67.
    Chan SL, Sweet JG, Cipolla MJ. Treatment for cerebral small vessel disease: effect of relaxin on the function and structure of cerebral parenchymal arterioles during hypertension. FASEB J. 2013;27:3917–27.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Cipolla MJ, Bullinger LV. Reactivity of brain parenchymal arterioles after ischemia and reperfusion. Microcirculation. 2008;15:495–501.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Nakahata K, Kinoshita H, Azma T, Matsuda N, Hama-Tomioka K, Haba M, et al. Propofol restores brain microvascular function impaired by high glucose via the decrease in oxidative stress. Anesthesiology. 2008;108:269–75.PubMedCrossRefGoogle Scholar
  70. 70.
    Gauthier KM, Campbell WB, McNeish AJ. Regulation of KCa2.3 and endothelium-dependent hyperpolarization (EDH) in the rat middle cerebral artery: the role of lipoxygenase metabolites and isoprostanes. Peer J. 2014;2:414.Google Scholar
  71. 71.
    Mayhan WG. Role of prostaglandin H2-thromboxane A2 in responses of cerebral arterioles during chronic hypertension. Am J Physiol. 1992;262:H539–43.PubMedGoogle Scholar
  72. 72.
    Mayhan WG, Faraci FM, Heistad DD. Responses of cerebral arterioles to adenosine 5′-diphosphate, serotonin, and the thromboxane analogue U-46619 during chronic hypertension. Hypertension. 1988;12:556–61.PubMedCrossRefGoogle Scholar
  73. 73.
    Mayhan WG, Simmons LK, Sharpe GM. Mechanism of impaired responses of cerebral arterioles during diabetes mellitus. Am J Physiol. 1991;260:H319–26.PubMedGoogle Scholar
  74. 74.
    De Caterina R, Libby P, Peng HB, Thannickal VJ, Rajavashisth TB, Gimbrone Jr MA, et al. Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Invest. 1995;96:60–8.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Shimokawa H, Satoh K. Light and dark of reactive oxygen species for vascular function. J Cardiovasc Pharmacol. 2015;65:412–8.Google Scholar
  76. 76.
    Dong M, Yan BP, Liao JK, Lam YY, Yip GW, Yu CM. Rho-kinase inhibition: a novel therapeutic target for the treatment of cardiovascular diseases. Drug Disc Today. 2010;15:622–9.CrossRefGoogle Scholar
  77. 77.
    Sawada N, Liao JK. Rho/Rho-associated coiled-coil forming kinase pathway as therapeutic targets for statins in atherosclerosis. Antioxid Redox Signal. 2014;20:1251–67.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Didion SP, Lynch CM, Baumbach GL, Faraci FM. Impaired endothelium-dependent responses and enhanced influence of Rho-kinase in cerebral arterioles in type II diabetes. Stroke. 2005;36:342–7.PubMedCrossRefGoogle Scholar
  79. 79.
    Iadecola C, Zhang F, Niwa K, Eckman C, Turner SK, Fischer E, et al. SOD1 rescues cerebral endothelial dysfunction in mice overexpressing amyloid precursor protein. Nat Neurosci. 1999;2:157–61.PubMedCrossRefGoogle Scholar
  80. 80.
    Zhang L, Papadopoulos P, Hamel E. Endothelial TRPV4 channels mediate dilation of cerebral arteries: impairment and recovery in cerebrovascular pathologies related to Alzheimer's disease. Br J Pharmacol. 2013;170:661–70.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Faraci F. Cerebral vascular dysfunction with aging. In: Masoro EJ, Austad S, editors. Handbook of the biology of aging. 7th ed. New York, NY: Academic; 2011. p. 405–18.CrossRefGoogle Scholar
  82. 82.
    Katusic ZS, Marshall JJ, Kontos HA, Vanhoutte PM. Similar responsiveness of smooth muscle of the canine basilar artery to EDRF and nitric oxide. Am J Physiol. 1989;257:H1235–9.PubMedGoogle Scholar
  83. 83.
    Kontos HA, Wei EP, Marshall JJ. In vivo bioassay of endothelium-derived relaxing factor. Am J Physiol. 1988;255:H1259–62.PubMedGoogle Scholar
  84. 84.
    Nelson CW, Wei EP, Povlishock JT, Kontos HA, Moskowitz MA. Oxygen radicals in cerebral ischemia. Am J Physiol. 1992;263:H1356–62.PubMedGoogle Scholar
  85. 85.
    Modrick ML, Didion SP, Lynch CM, Dayal S, Lentz SR, Faraci FM. Role of hydrogen peroxide and the impact of glutathione peroxidase-1 in regulation of cerebral vascular tone. J Cereb Blood Flow Metab. 2009;29:1130–7.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Bryan Jr RM, You J, Golding EM, Marrelli SP. Endothelium-derived hyperpolarizing factor: a cousin to nitric oxide and prostacyclin. Anesthesiology. 2005;102:1261–77.PubMedCrossRefGoogle Scholar
  87. 87.
    Dunn KM, Nelson MT. Neurovascular signaling in the brain and the pathological consequences of hypertension. Am J Physiol. 2014;306:H1–14.CrossRefGoogle Scholar
  88. 88.
    Iadecola C. The pathobiology of vascular dementia. Neuron. 2013;80:844–66.PubMedCrossRefGoogle Scholar
  89. 89.
    Chen BR, Kozberg MG, Bouchard MB, Shaik MA, Hillman EM. A critical role for the vascular endothelium in functional neurovascular coupling in the brain. J Am Heart Assoc. 2014;3:e000787.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Faraci FM, Heistad DD. Regulation of large cerebral arteries and cerebral microvascular pressure. Circ Res. 1990;66:8–17.PubMedCrossRefGoogle Scholar
  91. 91.
    Fujii K, Heistad DD, Faraci FM. Flow-mediated dilatation of the basilar artery in vivo. Circ Res. 1991;69:697–705.PubMedCrossRefGoogle Scholar
  92. 92.
    Joutel A, Faraci FM. Cerebral small vessel disease: insights and opportunities from mouse models of collagen IV-related small vessel disease and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Stroke. 2014;45:1215–21.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Vetri F, Xu H, Paisansathan C, Pelligrino DA. Impairment of neurovascular coupling in type 1 diabetes mellitus in rats is linked to PKC modulation of BKCa and Kir channels. Am J Physiol. 2012;302:H1274–84.Google Scholar
  94. 94.
    Kazama K, Wang G, Frys K, Anrather J, Iadecola C. Angiotensin II attenuates functional hyperemia in the mouse somatosensory cortex. Am J Physiol. 2003;285:H1890–9.Google Scholar
  95. 95.
    Jackman K, Iadecola C. Neurovascular regulation in the ischemic brain. Antioxid Redox Signal. 2015;22:149–60.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Park L, Koizumi K, El Jamal S, Zhou P, Previti ML, Van Nostrand WE, et al. Age-dependent neurovascular dysfunction and damage in a mouse model of cerebral amyloid angiopathy. Stroke. 2014;45:1815–21.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Dabertrand F, Hannah RM, Pearson JM, Hill-Eubanks DC, Brayden JE, Nelson MT. Prostaglandin E2, a postulated astrocyte-derived neurovascular coupling agent, constricts rather than dilates parenchymal arterioles. J Cereb Blood Flow Metab. 2013;33:479–82.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Shi Y, Liu X, Gebremedhin D, Falck JR, Harder DR, Koehler RC. Interaction of mechanisms involving epoxyeicosatrienoic acids, adenosine receptors, and metabotropic glutamate receptors in neurovascular coupling in rat whisker barrel cortex. J Cereb Blood Flow Metab. 2008;28:111–25.PubMedCrossRefGoogle Scholar
  99. 99.
    Gebremedhin D, Weinberger B, Lourim D, Harder DR. Adenosine can mediate its actions through generation of reactive oxygen species. J Cereb Blood Flow Metab. 2010;30:1777–90.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Brian Jr JE. Carbon dioxide and the cerebral circulation. Anesthesiology. 1998;88:1365–86.PubMedCrossRefGoogle Scholar
  101. 101.
    Kontos HA, Wei EP, Raper AJ, Patterson Jr JL. Local mechanism of CO2 action of cat pial arterioles. Stroke. 1977;8:226–9.PubMedCrossRefGoogle Scholar
  102. 102.
    Niwa K, Haensel C, Ross ME, Iadecola C. Cyclooxygenase-1 participates in selected vasodilator responses of the cerebral circulation. Circ Res. 2001;88:600–8.PubMedCrossRefGoogle Scholar
  103. 103.
    Leffler CW, Mirro R, Thompson C, Shibata M, Armstead WM, Pourcyrous M, et al. Activated oxygen species do not mediate hypercapnia-induced cerebral vasodilation in newborn pigs. Am J Physiol. 1991;261:H335–42.PubMedGoogle Scholar
  104. 104.
    Zhang F, Slungaard A, Vercellotti GM, Iadecola C. Superoxide-dependent cerebrovascular effects of homocysteine. Am J Physiol. 1998;274:R1704–11.PubMedGoogle Scholar
  105. 105.
    Niwa K, Carlson GA, Iadecola C. Exogenous A beta1-40 reproduces cerebrovascular alterations resulting from amyloid precursor protein overexpression in mice. J Cereb Blood Flow Metab. 2000;20:1659–68.PubMedCrossRefGoogle Scholar
  106. 106.
    Cipolla MJ. The cerebral circulation. Integrated systems physiology: from molecule to function. San Rafael, CA: Morgan & Claypool Life Sciences; 2009. p. 1–59.Google Scholar
  107. 107.
    Faraci FM, Baumbach GL, Heistad DD. Myogenic mechanisms in the cerebral circulation. J Hypertens. 1989;7:S61–4.Google Scholar
  108. 108.
    Kontos HA, Wei EP, Dietrich WD, Navari RM, Povlishock JT, Ghatak NR, et al. Mechanism of cerebral arteriolar abnormalities after acute hypertension. Am J Physiol. 1981;240:H511–27.PubMedGoogle Scholar
  109. 109.
    Wei EP, Kontos HA, Dietrich WD, Povlishock JT, Ellis EF. Inhibition by free radical scavengers and by cyclooxygenase inhibitors of pial arteriolar abnormalities from concussive brain injury in cats. Circ Res. 1981;48:95–103.PubMedCrossRefGoogle Scholar
  110. 110.
    Gebremedhin D, Terashvili M, Wickramasekera N, Zhang DX, Rau N, Miura H, et al. Redox signaling via oxidative inactivation of PTEN modulates pressure-dependent myogenic tone in rat middle cerebral arteries. PLoS One. 2013;8, e68498.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Lim M, Choi SK, Cho YE, Yeon SI, Kim EC, Ahn DS, et al. The role of sphingosine kinase 1/sphingosine-1-phosphate pathway in the myogenic tone of posterior cerebral arteries. PLoS One. 2012;7, e35177.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Butcher JT, Goodwill AG, Stanley SC, Frisbee JC. Differential impact of dilator stimuli on increased myogenic activation of cerebral and skeletal muscle resistance arterioles in obese zucker rats. Microcirculation. 2013;20:579–89.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Phillips SA, Sylvester FA, Frisbee JC. Oxidant stress and constrictor reactivity impair cerebral artery dilation in obese Zucker rats. Am J Physiol. 2005;288:R522–30.Google Scholar
  114. 114.
    Didion SP, Ryan MJ, Didion LA, Fegan PE, Sigmund CD, Faraci FM. Increased superoxide and vascular dysfunction in CuZnSOD-deficient mice. Circ Res. 2002;91:938–44.PubMedCrossRefGoogle Scholar
  115. 115.
    Faraci FM, Modrick ML, Lynch CM, Didion LA, Fegan PE, Didion SP. Selective cerebral vascular dysfunction in Mn-SOD-deficient mice. J Appl Physiol. 2006;100:2089–93.PubMedCrossRefGoogle Scholar
  116. 116.
    Kitayama J, Yi C, Faraci FM, Heistad DD. Modulation of dilator responses of cerebral arterioles by extracellular superoxide dismutase. Stroke. 2006;37:2802–6.PubMedCrossRefGoogle Scholar
  117. 117.
    Brown KA, Didion SP, Andresen JJ, Faraci FM. Effect of aging, MnSOD deficiency, and genetic background on endothelial function: evidence for MnSOD haploinsufficiency. Arterioscler Thromb Vasc Biol. 2007;27:1941–6.PubMedCrossRefGoogle Scholar
  118. 118.
    Chrissobolis S, Faraci FM. Sex differences in protection against angiotensin II-induced endothelial dysfunction by manganese superoxide dismutase in the cerebral circulation. Hypertension. 2010;55:905–10.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Didion SP, Kinzenbaw DA, Faraci FM. Critical role for CuZn-superoxide dismutase in preventing angiotensin II-induced endothelial dysfunction. Hypertension. 2005;46:1147–53.PubMedCrossRefGoogle Scholar
  120. 120.
    Chrissobolis S, Didion SP, Kinzenbaw DA, Schrader LI, Dayal S, Lentz SR, et al. Glutathione peroxidase-1 plays a major role in protecting against angiotensin II-induced vascular dysfunction. Hypertension. 2008;51:872–7.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Ketsawatsomkron P, Pelham CJ, Groh S, Keen HL, Faraci FM, Sigmund CD. Does peroxisome proliferator-activated receptor-gamma protect from hypertension directly through effects in the vasculature? J Biol Chem. 2010;285:9311–6.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Marchesi C, Schiffrin EL. Peroxisome proliferator-activated receptors and the vascular system: beyond their metabolic effects. J Am Soc Hypertens. 2008;2:227–38.PubMedCrossRefGoogle Scholar
  123. 123.
    Plutzky J. The PPAR-RXR transcriptional complex in the vasculature: energy in the balance. Circ Res. 2011;108:1002–16.PubMedCrossRefGoogle Scholar
  124. 124.
    Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA. 2007;298:1180–8.PubMedCrossRefGoogle Scholar
  125. 125.
    Ryan MJ, Didion SP, Mathur S, Faraci FM, Sigmund CD. PPAR gamma agonist rosiglitazone improves vascular function and lowers blood pressure in hypertensive transgenic mice. Hypertension. 2004;43:661–6.PubMedCrossRefGoogle Scholar
  126. 126.
    Cipolla MJ, Bishop N, Vinke RS, Godfrey JA. PPAR gamma activation prevents hypertensive remodeling of cerebral arteries and improves vascular function in female rats. Stroke. 2010;41:1266–70.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Barroso I, Gurnell M, Crowley VE, Agostini M, Schwabe JW, Soos MA, et al. Dominant negative mutations in human PPAR gamma associated with severe insulin resistance, diabetes mellitus and hypertension. Nature. 1999;402:880–3.PubMedGoogle Scholar
  128. 128.
    Keen HL, Halabi CM, Beyer AM, de Lange WJ, Liu X, Maeda N, et al. Bioinformatic analysis of gene sets regulated by ligand-activated and dominant-negative peroxisome proliferator-activated receptor gamma in mouse aorta. Arterioscler Thromb Vasc Biol. 2010;30:518–25.PubMedCrossRefGoogle Scholar
  129. 129.
    Beyer AM, Baumbach GL, Halabi CM, Modrick ML, Lynch CM, Gerhold TD, et al. Interference with PPAR gamma signaling causes cerebral vascular dysfunction, hypertrophy, and remodeling. Hypertension. 2008;51:867–71.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Beyer AM, de Lange WJ, Halabi CM, Modrick ML, Keen HL, Faraci FM, et al. Endothelium-specific interference with peroxisome proliferator activated receptor gamma causes cerebral vascular dysfunction in response to a high-fat diet. Circ Res. 2008;103:654–61.PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Lyle AN, Griendling KK. Modulation of vascular smooth muscle signaling by reactive oxygen species. Physiology. 2006;21:269–80.PubMedCrossRefGoogle Scholar
  132. 132.
    Reckelhoff JF, Romero JC. Role of oxidative stress in angiotensin-induced hypertension. Am J Physiol. 2003;284:R893–912.Google Scholar
  133. 133.
    Balakumar P, Jagadeesh G. A century old renin-angiotensin system still grows with endless possibilities: a T receptor signaling cascades in cardiovascular physiopathology. Cell Signal. 2014;26:2147–60.PubMedCrossRefGoogle Scholar
  134. 134.
    Santos RA. Angiotensin-(1–7). Hypertension. 2014;63:1138–47.PubMedCrossRefGoogle Scholar
  135. 135.
    Pena Silva RA, Chu Y, Miller JD, Mitchell IJ, Penninger JM, Faraci FM, et al. Impact of ACE2 deficiency and oxidative stress on cerebrovascular function with aging. Stroke. 2012;43:3358–63.PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Higashi Y, Maruhashi T, Noma K, Kihara Y. Oxidative stress and endothelial dysfunction: clinical evidence and therapeutic implications. Trends Cardiovasc Med. 2014;24:165–9.PubMedCrossRefGoogle Scholar
  137. 137.
    Rodriguez-Manas L, El-Assar M, Vallejo S, Lopez-Doriga P, Solis J, Petidier R, et al. Endothelial dysfunction in aged humans is related with oxidative stress and vascular inflammation. Aging Cell. 2009;8:226–38.PubMedCrossRefGoogle Scholar
  138. 138.
    Wray DW, Nishiyama SK, Harris RA, Zhao J, McDaniel J, Fjeldstad AS, et al. Acute reversal of endothelial dysfunction in the elderly after antioxidant consumption. Hypertension. 2012;59:818–24.PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Heart Protection Study Collaborative G. MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:23–33.CrossRefGoogle Scholar
  140. 140.
    Yamada M, Lamping KG, Duttaroy A, Zhang W, Cui Y, Bymaster FP, et al. Cholinergic dilation of cerebral blood vessels is abolished in M5 muscarinic acetylcholine receptor knockout mice. Proc Natl Acad Sci. 2001;98:14096–101.PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Sullivan MN, Earley S. TRP channel Ca2+ sparklets: fundamental signals underlying endothelium-dependent hyperpolarization. Am J Physiol. 2013;305:C999–1008.CrossRefGoogle Scholar
  142. 142.
    Ngai AC, Winn HR. Modulation of cerebral arteriolar diameter by intraluminal flow and pressure. Circ Res. 1995;77:832–40.PubMedCrossRefGoogle Scholar
  143. 143.
    Ago T, Kitazono T, Kuroda J, Kumai Y, Kamouchi M, Ooboshi H, et al. NAD(P)H oxidases in rat basilar arterial endothelial cells. Stroke. 2005;36:1040–6.PubMedCrossRefGoogle Scholar
  144. 144.
    Paravicini TM, Chrissobolis S, Drummond GR, Sobey CG. Increased NADPH-oxidase activity and Nox4 expression during chronic hypertension is associated with enhanced cerebral vasodilatation to NADPH in vivo. Stroke. 2004;35:584–9.PubMedCrossRefGoogle Scholar
  145. 145.
    Fang Q, Sun H, Arrick DM, Mayhan WG. Inhibition of NADPH oxidase improves impaired reactivity of pial arterioles during chronic exposure to nicotine. J Appl Physiol. 2006;100:631–6.PubMedCrossRefGoogle Scholar
  146. 146.
    Mayhan WG, Arrick DM, Sharpe GM, Patel KP, Sun H. Inhibition of NAD(P)H oxidase alleviates impaired NOS-dependent responses of pial arterioles in type 1 diabetes mellitus. Microcirculation. 2006;13:567–75.PubMedCrossRefGoogle Scholar
  147. 147.
    Miller AA, Drummond GR, Mast AE, Schmidt HH, Sobey CG. Effect of gender on NADPH-oxidase activity, expression, and function in the cerebral circulation: role of estrogen. Stroke. 2007;38:2142–9.PubMedCrossRefGoogle Scholar
  148. 148.
    De Silva TM, Broughton BR, Drummond GR, Sobey CG, Miller AA. Gender influences cerebral vascular responses to angiotensin II through Nox2-derived reactive oxygen species. Stroke. 2009;40:1091–7.PubMedCrossRefGoogle Scholar
  149. 149.
    Miller AA, De Silva TM, Judkins CP, Diep H, Drummond GR, Sobey CG. Augmented superoxide production by Nox2-containing NADPH oxidase causes cerebral artery dysfunction during hypercholesterolemia. Stroke. 2010;41:784–9.PubMedCrossRefGoogle Scholar
  150. 150.
    Kleinschnitz C, Grund H, Wingler K, Armitage ME, Jones E, Mittal M, et al. Post-stroke inhibition of induced NADPH oxidase type 4 prevents oxidative stress and neurodegeneration. PLoS Biol. 2010;8.Google Scholar
  151. 151.
    Akopov SE, Grigorian MR, Gabrielian ES. The endothelium-dependent relaxation of human middle cerebral artery: effects of activated neutrophils. Experientia. 1992;48:34–6.PubMedCrossRefGoogle Scholar
  152. 152.
    Wei EP, Kontos HA, Christman CW, DeWitt DS, Povlishock JT. Superoxide generation and reversal of acetylcholine-induced cerebral arteriolar dilation after acute hypertension. Circ Res. 1985;57:781–7.PubMedCrossRefGoogle Scholar
  153. 153.
    Mayhan WG, Arrick DM, Sharpe GM, Sun H. Age-related alterations in reactivity of cerebral arterioles: role of oxidative stress. Microcirculation. 2008;15:225–36.PubMedCrossRefGoogle Scholar
  154. 154.
    Sun H, Mayhan WG. Temporal effect of alcohol consumption on reactivity of pial arterioles: role of oxygen radicals. Am J Physiol. 2001;280:H992–1001.Google Scholar
  155. 155.
    Sun H, Zheng H, Molacek E, Fang Q, Patel KP, Mayhan WG. Role of NAD(P)H oxidase in alcohol-induced impairment of endothelial nitric oxide synthase-dependent dilation of cerebral arterioles. Stroke. 2006;37:495–500.PubMedCrossRefGoogle Scholar
  156. 156.
    Sun H, Mayhan WG. Superoxide dismutase ameliorates impaired nitric oxide synthase-dependent dilatation of the basilar artery during chronic alcohol consumption. Brain Res. 2001;891:116–22.PubMedCrossRefGoogle Scholar
  157. 157.
    Tong XK, Nicolakakis N, Kocharyan A, Hamel E. Vascular remodeling versus amyloid beta-induced oxidative stress in the cerebrovascular dysfunctions associated with Alzheimer's disease. J Neurosci. 2005;25:11165–74.PubMedCrossRefGoogle Scholar
  158. 158.
    Capone C, Faraco G, Anrather J, Zhou P, Iadecola C. Cyclooxygenase 1-derived prostaglandin E2 and EP1 receptors are required for the cerebrovascular dysfunction induced by angiotensin II. Hypertension. 2010;55:911–7.PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Capone C, Faraco G, Park L, Cao X, Davisson RL, Iadecola C. The cerebrovascular dysfunction induced by slow pressor doses of angiotensin-II precedes the development of hypertension. Am J Physiol. 2011;300:H397–407.CrossRefGoogle Scholar
  160. 160.
    Johnson AW, Kinzenbaw DA, Modrick ML, Faraci FM. Small-molecule inhibitors of signal transducer and activator of transcription 3 protect against angiotensin II-induced vascular dysfunction and hypertension. Hypertension. 2013;61:437–42.PubMedCrossRefGoogle Scholar
  161. 161.
    Faraci FM, Lamping KG, Modrick ML, Ryan MJ, Sigmund CD, Didion SP. Cerebral vascular effects of angiotensin II: new insights from genetic models. J Cereb Blood Flow Metab. 2006;26:449–55.PubMedCrossRefGoogle Scholar
  162. 162.
    Gibson CC, Zhu W, Davis CT, Bowman-Kirigin JA, Chan AC, Ling J, et al. Strategy for identifying repurposed drugs for the treatment of cerebral cavernous malformation. Circulation. 2015;131(3):289–99.PubMedCrossRefGoogle Scholar
  163. 163.
    Faraco G, Wijasa TS, Park L, Moore J, Anrather J, Iadecola C. Water deprivation induces neurovascular and cognitive dysfunction through vasopressin-induced oxidative stress. J Cereb Blood Flow Metab. 2014;34:852–60.PubMedPubMedCentralCrossRefGoogle Scholar
  164. 164.
    Mayhan WG. Superoxide dismutase partially restores impaired dilatation of the basilar artery during diabetes mellitus. Brain Res. 1997;760:204–9.PubMedCrossRefGoogle Scholar
  165. 165.
    Didion SP, Lynch CM, Faraci FM. Cerebral vascular dysfunction in TallyHo mice: a new model of type II diabetes. Am J Physiol. 2007;292:H1579–83.Google Scholar
  166. 166.
    Matsumoto T, Kobayashi T, Wachi H, Seyama Y, Kamata K. Vascular NAD(P)H oxidase mediates endothelial dysfunction in basilar arteries from Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Atherosclerosis. 2007;192:15–24.PubMedCrossRefGoogle Scholar
  167. 167.
    Erdos B, Snipes JA, Miller AW, Busija DW. Cerebrovascular dysfunction in Zucker obese rats is mediated by oxidative stress and protein kinase C. Diabetes. 2004;53:1352–9.PubMedCrossRefGoogle Scholar
  168. 168.
    De Silva TM, Lynch CM, Grobe JL, Faraci FM. Activation of the central renin angiotensin system (RAS) causes selective cerebrovascular dysfunction (Abstract). FASEB J. 2015;29:646–4.Google Scholar
  169. 169.
    Kontos HA, Wei EP. Endothelium-dependent responses after experimental brain injury. J Neurotrauma. 1992;9:349–54.PubMedCrossRefGoogle Scholar
  170. 170.
    Kitayama J, Faraci FM, Lentz SR, Heistad DD. Cerebral vascular dysfunction during hypercholesterolemia. Stroke. 2007;38:2136–41.PubMedCrossRefGoogle Scholar
  171. 171.
    Dayal S, Arning E, Bottiglieri T, Boger RH, Sigmund CD, Faraci FM, et al. Cerebral vascular dysfunction mediated by superoxide in hyperhomocysteinemic mice. Stroke. 2004;35:1957–62.PubMedCrossRefGoogle Scholar
  172. 172.
    Xie H, Ray PE, Short BL. NF-kappaB activation plays a role in superoxide-mediated cerebral endothelial dysfunction after hypoxia/reoxygenation. Stroke. 2005;36:1047–52.PubMedCrossRefGoogle Scholar
  173. 173.
    Capone C, Faraco G, Coleman C, Young CN, Pickel VM, Anrather J, et al. Endothelin 1-dependent neurovascular dysfunction in chronic intermittent hypoxia. Hypertension. 2012;60:106–13.PubMedPubMedCentralCrossRefGoogle Scholar
  174. 174.
    Kunz A, Park L, Abe T, Gallo EF, Anrather J, Zhou P, et al. Neurovascular protection by ischemic tolerance: role of nitric oxide and reactive oxygen species. J Neurosci. 2007;27:7083–93.PubMedCrossRefGoogle Scholar
  175. 175.
    Hernanz R, Briones AM, Alonso MJ, Vila E, Salaices M. Hypertension alters role of iNOS, COX-2, and oxidative stress in bradykinin relaxation impairment after LPS in rat cerebral arteries. Am J Physiol. 2004;287:H225–34.Google Scholar
  176. 176.
    Mayhan WG, Arrick DM, Sharpe GM, Sun H. Nitric oxide synthase-dependent responses of the basilar artery during acute infusion of nicotine. Nicotine Tob Res. 2009;11:270–7.PubMedPubMedCentralCrossRefGoogle Scholar
  177. 177.
    Zhang R, Bai YG, Lin LJ, Bao JX, Zhang YY, Tang H, et al. Blockade of AT1 receptor partially restores vasoreactivity, NOS expression, and superoxide levels in cerebral and carotid arteries of hindlimb unweighting rats. J Appl Physiol. 2009;106:251–8.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Departments of Internal Medicine and Pharmacology, Francois M. Abboud Cardiovascular Center, Carver College of MedicineUniversity of IowaIowa CityUSA
  2. 2.Iowa City Veterans Affairs Healthcare SystemIowa CityUSA

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