Cerebral small vessel disease: Targeting oxidative stress as a novel therapeutic strategy?

Frontiers in Pharmacology

Volumn 7, Issue MAR, 2016, Pages

  De Silva, T Michael ^a   Miller, Alyson A ^b  

^a MONASH UNIVERSITY   (Australia)

^b RMIT UNIVERSITY   (Australia)

Author keywords

Brain injury; Cerebral small vessel disease; Cognitive impairment; NADPH oxidases (Noxs); Oxidative stress and redox regulation; Pharmacological strategies

Indexed keywords

ALPHA TOCOPHEROL; ALTEPLASE; AMYLOID BETA PROTEIN; ANGIOTENSIN 1 RECEPTOR; ANGIOTENSIN II; ANTIHYPERTENSIVE AGENT; ASCORBIC ACID; DISUFENTON SODIUM; ENDOTHELIAL NITRIC OXIDE SYNTHASE; ENDOTHELIN 1; GELATINASE B; GKT 136901; GLUTATHIONE PEROXIDASE; HYDROGEN PEROXIDE; NICOTINAMIDE ADENINE DINUCLEOTIDE ADENOSINE DIPHOSPHATE RIBOSYLTRANSFERASE; PROSTAGLANDIN SYNTHASE; PROTEIN ZO1; PYRIMIDINE DERIVATIVE; REACTIVE OXYGEN METABOLITE; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE 2; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE 3; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE 4; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE 5; RHO KINASE; TRANSIENT RECEPTOR POTENTIAL CHANNEL 2; TRANSIENT RECEPTOR POTENTIAL CHANNEL M2; UNCLASSIFIED DRUG; UNINDEXED DRUG; VAS 2870; VAS 3947;

AGING; BLOOD BRAIN BARRIER; BRAIN HEMORRHAGE; BRAIN INJURY; CARDIOVASCULAR RISK; CEREBROVASCULAR ACCIDENT; CEREBROVASCULAR DISEASE; CLINICAL EFFECTIVENESS; CLINICAL FEATURE; COGNITIVE DEFECT; DISEASE CLASSIFICATION; ENZYME ACTIVITY; ENZYME INHIBITION; GENE DELETION; HUMAN; HYPERTENSION; LACUNAR STROKE; NONHUMAN; NUCLEAR MAGNETIC RESONANCE IMAGING; OXIDATIVE STRESS; PATHOGENESIS; PROTEIN EXPRESSION; REVIEW; RISK FACTOR; VASCULAR AMYLOIDOSIS;

EID: 84966710973     PISSN: None     EISSN: 16639812     Source Type: Journal    
DOI: 10.3389/fphar.2016.00061     Document Type: Review

References (224)

1. Aghajanian, A., Wittchen, E. S., Campbell, S. L., and Burridge, K. (2009). Direct activation of RhoA by reactive oxygen species requires a redox-sensitive motif. PLoS ONE 4:e8045. doi: 10.1371/journal.pone.0008045
2. Ago, T., Kitazono, T., Kuroda, J., Kumai, Y., Kamouchi, M., Ooboshi, H., et al. (2005). NAD(P)H oxidases in rat basilar arterial endothelial cells. Stroke 36, 1040-1046. doi: 10.1161/01.STR.0000163111.05825.0b
3. Allen, C. L., and Bayraktutan, U. (2009). Oxidative stress and its role in the pathogenesis of ischaemic stroke. Int. J. Stroke 4, 461-470. doi: 10.1111/j.1747-4949.2009.00387.x
4. Altenhofer, S., Radermacher, K. A., Kleikers, P. W., Wingler, K., and Schmidt, H. H. (2015). Evolution of NADPH oxidase inhibitors: selectivity and mechanisms for target engagement. Antioxid. Redox Signal. 23, 406-427. doi: 10.1089/ars.2013.5814
5. Amarenco, P., Benavente, O., Goldstein, L. B., Callahan, A. III, Sillesen, H., Hennerici, M. G., et al. (2009). Results of the stroke prevention by aggressive reduction in cholesterol levels (SPARCL) trial by stroke subtypes. Stroke 40, 1405-1409. doi: 10.1161/STROKEAHA.108.534107
6. Aribisala, B. S., Valdes Hernandez, M. C., Royle, N. A., Morris, Z., Munoz Maniega, S., Bastin, M. E., et al. (2013). Brain atrophy associations with white matter lesions in the ageing brain: the Lothian Birth Cohort 1936. Eur. Radiol. 23, 1084-1092. doi: 10.1007/s00330-012-2677-x
7. Arrick, D. M., Sharpe, G. M., Sun, H., and Mayhan, W. G. (2007). Diabetes-induced cerebrovascular dysfunction: role of poly (ADP-ribose) polymerase. Microvasc. Res. 73, 1-6. doi: 10.1016/j.mvr.2006.08.001
8. Arrick, D. M., Sharpe, G. M., Sun, H., and Mayhan, W. G. (2008). Losartan improves impaired nitric oxide synthase-dependent dilatation of cerebral arterioles in type 1 diabetic rats. Brain Res. 1209, 128-135. doi: 10.1016/j.brainres.2008.03.020
9. Attems, J. (2005). Sporadic cerebral amyloid angiopathy: pathology, clinical implications, and possible pathomechanisms. Acta Neuropathol. 110, 345-359. doi: 10.1007/s00401-005-1074-9
10. Attwell, D., Buchan, A. M., Charpak, S., Lauritzen, M., Macvicar, B. A., and Newman, E. A. (2010). Glial and neuronal control of brain blood flow. Nature 468, 232-243. doi: 10.1038/nature09613
11. Babior, B. M., Lambeth, J. D., and Nauseef, W. (2002). The neutrophil NADPH oxidase. Arch. Biochem. Biophys. 397, 342-344. doi: 10.1006/abbi.2001.2642
12. Bastin, M. E., Clayden, J. D., Pattie, A., Gerrish, I. F., Wardlaw, J. M., and Deary, I. J. (2009). Diffusion tensor and magnetization transfer MRI measurements of periventricular white matter hyperintensities in old age. Neurobiol. Aging 30, 125-136. doi: 10.1016/j.neurobiolaging.2007.05.013
13. Bath, P. M., and Wardlaw, J. M. (2015). Pharmacological treatment and prevention of cerebral small vessel disease: a review of potential interventions. Int. J. Stroke 10, 469-478. doi: 10.1111/ijs.12466
14. Baumbach, G., and Heistad, D. (1989). Remodeling of cerebral arterioles in chronic hypertension. Hypertension 13, 968-972. doi: 10.1161/01.HYP.13.6.968
15. Baumbach, G. L., Sigmund, C. D., and Faraci, F. M. (2003). Cerebral arteriolar structure in mice overexpressing human renin and angiotensinogen. Hypertension 41, 50-55. doi: 10.1161/01.HYP.0000042427.05390.5C
16. Bedard, K., and Jaquet, V. (2012). Cell-free screening for NOX inhibitors. Chem. Biol. 19, 664-665. doi: 10.1016/j.chembiol.2012.06.002
17. Bedard, K., Whitehouse, S., and Jaquet, V. (2015). Challenges, progresses, and promises for developing future nadph oxidase therapeutics. Antioxid. Redox Signal. 23, 355-357. doi: 10.1089/ars.2015.6450
18. Bell, R. D., Winkler, E. A., Sagare, A. P., Singh, I., LaRue, B., Deane, R., et al. (2010). Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron 68, 409-427. doi: 10.1016/j.neuron.2010.09.043
19. Benavente, O. R., Coffey, C. S., Conwit, R., Hart, R. G., McClure, L. A., Pearce, L. A., et al. (2013). Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial. Lancet 382, 507-515. doi: 10.1016/S0140-6736(13)60852-1
20. Benavente, O. R., Hart, R. G., McClure, L. A., Szychowski, J. M., Coffey, C. S., and Pearce, L. A. (2012). Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. N. Engl. J. Med. 367, 817-825. doi: 10.1056/NEJMoa1204133
21. Bhandarkar, S. S., Jaconi, M., Fried, L. E., Bonner, M. Y., Lefkove, B., Govindarajan, B., et al. (2009). Fulvene-5 potently inhibits NADPH oxidase 4 and blocks the growth of endothelial tumors in mice. J. Clin. Invest. 119, 2359-2365. doi: 10.1172/JCI33877
22. Brait, V. H., Jackman, K. A., Walduck, A. K., Selemidis, S., Diep, H., Mast, A. E., et al. (2010). Mechanisms contributing to cerebral infarct size after stroke: gender, reperfusion, T lymphocytes, and Nox2-derived superoxide. J. Cereb. Blood Flow Metabol. 30, 1306-1317. doi: 10.1038/jcbfm.2010.14
23. Briviba, K., Roussyn, I., Sharov, V. S., and Sies, H. (1996). Attenuation of oxidation and nitration reactions of peroxynitrite by selenomethionine, selenocystine and ebselen. Biochem. J. 319(Pt 1), 13-15. doi: 10.1042/bj3190013
24. Brown, W. R., Moody, D. M., Thore, C. R., Challa, V. R., and Anstrom, J. A. (2007). Vascular dementia in leukoaraiosis may be a consequence of capillary loss not only in the lesions, but in normal-appearing white matter and cortex as well. J. Neurol. Sci. 257, 62-66. doi: 10.1016/j.jns.2007.01.015
25. Bruinsma, I. B., Wilhelmus, M. M., Kox, M., Veerhuis, R., de Waal, R. M., and Verbeek, M. M. (2010). Apolipoprotein E protects cultured pericytes and astrocytes from D-Abeta(1-40)-mediated cell death. Brain Res. 1315, 169-180. doi: 10.1016/j.brainres.2009.12.039
26. Budzyn, K., Marley, P. D., and Sobey, C. G. (2006). Targeting Rho and Rho-kinase in the treatment of cardiovascular disease. Trends Pharmacol. Sci. 27, 97-104. doi: 10.1016/j.tips.2005.12.002
27. Bullen, M. L., Miller, A. A., Andrews, K. L., Irvine, J. C., Ritchie, R. H., Sobey, C. G., et al. (2011). Nitroxyl (HNO) as a vasoprotective signaling molecule. Antioxid. Redox Signal. 14, 1675-1686. doi: 10.1089/ars.2010.3327
28. Bullmore, E., and Sporns, O. (2012). The economy of brain network organization. Nat. Rev. Neurosci. 13, 336-349. doi: 10.1038/nrn3214
29. Busija, D. W., and Katakam, P. V. (2014). Mitochondrial mechanisms in cerebral vascular control: shared signaling pathways with preconditioning. J. Vasc. Res. 51, 175-189. doi: 10.1159/000360765
30. Carrano, A., Hoozemans, J. J., van der Vies, S. M., Rozemuller, A. J., van Horssen, J., and de Vries, H. E. (2011). Amyloid Beta induces oxidative stress-mediated blood-brain barrier changes in capillary amyloid angiopathy. Antioxid. Redox Signal. 15, 1167-1178. doi: 10.1089/ars.2011.3895
31. Carrano, A., Hoozemans, J. J., van der Vies, S. M., van Horssen, J., de Vries, H. E., and Rozemuller, A. J. (2012). Neuroinflammation and blood-brain barrier changes in capillary amyloid angiopathy. Neuro Degener. Dis. 10, 329-331. doi: 10.1159/000334916
32. Cayatte, A. J., Rupin, A., Oliver-Krasinski, J., Maitland, K., Sansilvestri-Morel, P., Boussard, M. F., et al. (2001). S17834, a new inhibitor of cell adhesion and atherosclerosis that targets nadph oxidase. Arterioscler. Thromb. Vasc. Biol. 21, 1577-1584. doi: 10.1161/hq1001.096723
33. Chabriat, H., Vahedi, K., Bousser, M. G., Iba-Zizen, M. T., Joutel, A., Nibbio, A., et al. (1995). Clinical spectrum of CADASIL: a study of 7 families. Lancet 346, 934-939. doi: 10.1016/S0140-6736(95)91557-5
34. Chan, S. L., and Baumbach, G. L. (2013a). Nox2 deficiency prevents hypertension-induced vascular dysfunction and hypertrophy in cerebral arterioles. Int. J. Hypert. 2013:793630. doi: 10.1155/2013/793630
35. Chan, S. L., and Baumbach, G. L. (2013b). Deficiency of Nox2 prevents angiotensin II-induced inward remodeling in cerebral arterioles. Front. Physiol. 4:133. doi: 10.3389/fphys.2013.00133
36. Chan, S. L., Umesalma, S., and Baumbach, G. L. (2015). Epidermal growth factor receptor is critical for angiotensin II-mediated hypertrophy in cerebral arterioles. Hypertension 65, 806-812. doi: 10.1161/HYPERTENSIONAHA.114.04794
37. Chen, H., Song, Y. S., and Chan, P. H. (2009). Inhibition of NADPH oxidase is neuroprotective after ischemia-reperfusion. J. Cereb. Blood Flow Metabol. 29, 1262-1272. doi: 10.1038/jcbfm.2009.47
38. Choi, D. H., Kim, J. H., Lee, K. H., Kim, H. Y., Kim, Y. S., Choi, W. S., et al. (2015). Role of neuronal NADPH oxidase 1 in the peri-infarct regions after stroke. PLoS ONE 10:e0116814. doi: 10.1371/journal.pone.0116814
39. Choi, D. H., Lee, K. H., Kim, J. H., Seo, J. H., Kim, H. Y., Shin, C. Y., et al. (2014). NADPH oxidase 1, a novel molecular source of ROS in hippocampal neuronal death in vascular dementia. Antioxid. Redox Signal. 21, 533-550. doi: 10.1089/ars.2012.5129
40. Chrissobolis, S., Banfi, B., Sobey, C. G., and Faraci, F. M. (2012). Role of Nox isoforms in angiotensin II-induced oxidative stress and endothelial dysfunction in brain. J. Appl. Physiol. 113, 184-191. doi: 10.1152/japplphysiol.00455.2012
41. Christie, R., Yamada, M., Moskowitz, M., and Hyman, B. (2001). Structural and functional disruption of vascular smooth muscle cells in a transgenic mouse model of amyloid angiopathy. Am. J. Pathol. 158, 1065-1071. doi: 10.1016/S0002-9440(10)64053-9
42. Cipolla, M. J. (2009). "The cerebral circulation, " in Integrated Systems Physiology: from Molecule to Function, eds D. N. Granger and J. Granger (San Rafael: Morgan & Claypool Life Sciences), 1-59.
43. Csanyi, G., Cifuentes-Pagano, E., Al Ghouleh, I., Ranayhossaini, D. J., Egana, L., Lopes, L. R., et al. (2011). Nox2 B-loop peptide, Nox2ds, specifically inhibits the NADPH oxidase Nox2. Free Radical Biol. Med. 51, 1116-1125. doi: 10.1016/j.freeradbiomed.2011.04.025
44. Dayal, S., Arning, E., Bottiglieri, T., Boger, R. H., Sigmund, C. D., Faraci, F. M., et al. (2004). Cerebral Vascular dysfunction mediated by superoxide in hyperhomocysteinemic mice. Stroke 35, 1957-1962. doi: 10.1161/01.STR.0000131749.81508.18
45. Dayal, S., Devlin, A. M., McCaw, R. B., Liu, M. L., Arning, E., Bottiglieri, T., et al. (2005). Cerebral vascular dysfunction in methionine synthase-deficient mice. Circulation 112, 737-744. doi: 10.1161/CIRCULATIONAHA.104.529248
46. de Laat, K. F., Tuladhar, A. M., van Norden, A. G. W., Norris, D. G., Zwiers, M. P., and de Leeuw, F.-E. (2011). Loss of white matter integrity is associated with gait disorders in cerebral small vessel disease. Brain 134, 73-83. doi: 10.1093/brain/awq343
47. De Reuck, J., Deramecourt, V., Cordonnier, C., Leys, D., Maurage, C. A., and Pasquier, F. (2011). The impact of cerebral amyloid angiopathy on the occurrence of cerebrovascular lesions in demented patients with Alzheimer features: a neuropathological study. Eur. J. Neurol. 18, 913-918. doi: 10.1111/j.1468-1331.2010.03329.x
48. De Silva, T. M., Brait, V. H., Drummond, G. R., Sobey, C. G., and Miller, A. A. (2011). Nox2 oxidase activity accounts for the oxidative stress and vasomotor dysfunction in mouse cerebral arteries following ischemic stroke. PLoS ONE 6:e28393. doi: 10.1371/journal.pone.0028393
49. De Silva, T. M., Broughton, B. R., Drummond, G. R., Sobey, C. G., and Miller, A. A. (2009). Gender influences cerebral vascular responses to angiotensin II through Nox2-derived reactive oxygen species. Stroke 40, 1091-1097. doi: 10.1161/STROKEAHA.108.531707
50. De Silva, T. M., and Faraci, F. M. (2012). Effects of angiotensin II on the cerebral circulation: role of oxidative stress. Front. Physiol. 3:484. doi: 10.3389/fphys.2012.00484
51. De Silva, T. M., and Faraci, F. M. (in press). Microvascular dysfunction and cognitive impairment. Cell Mol. Neurosci.
52. Debette, S., and Markus, H. S. (2010). The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ 341:c3666. doi: 10.1136/bmj.c3666
53. Devlin, A. M., Arning, E., Bottiglieri, T., Faraci, F. M., Rozen, R., and Lentz, S. R. (2004). Effect of Mthfr genotype on diet-induced hyperhomocysteinemia and vascular function in mice. Blood 103, 2624-2629. doi: 10.1182/blood-2003-09-3078
54. Didion, S., Hathaway, C., and Faraci, F. (2001). Superoxide levels and function of cerebral blood vessels after inhibition of CuZn-SOD. Am. J. Physiol. Heart Circ. Physiol. 281, H1697-H1703.
55. Didion, S. P., and Faraci, F. M. (2002). Effects of NADH and NADPH on superoxide levels and cerebral vascular tone. Am. J. Physiol. Heart Circ. Physiol. 282, H688-H695. doi: 10.1152/ajpheart.00576.2001
56. Didion, S. P., Lynch, C. M., Baumbach, G. L., and Faraci, F. M. (2005). Impaired endothelium-dependent responses and enhanced influence of Rho-kinase in cerebral arterioles in type II diabetes. Stroke 36, 342-347. doi: 10.1161/01.STR.0000152952.42730.92
57. Didion, S. P., Lynch, C. M., and Faraci, F. M. (2007). Cerebral vascular dysfunction in TallyHo mice: a new model of Type II diabetes. Am. J. Physiol. Heart Circ. Physiol. 292, H1579-H1583. doi: 10.1152/ajpheart.00939.2006
58. Didion, S. P., Sigmund, C. D., and Faraci, F. M. (2000). Impaired endothelial function in transgenic mice expressing both human renin and human angiotensinogen. Stroke 31, 760-764. doi: 10.1161/01.STR.31.3.760
59. Dikalov, S. I., Dikalova, A. E., Bikineyeva, A. T., Schmidt, H. H., Harrison, D. G., and Griendling, K. K. (2008). Distinct roles of Nox1 and Nox4 in basal and angiotensin II-stimulated superoxide and hydrogen peroxide production. Free Radical Biol. Med. 45, 1340-1351. doi: 10.1016/j.freeradbiomed.2008.08.013
60. Dong, Y. F., Kataoka, K., Toyama, K., Sueta, D., Koibuchi, N., Yamamoto, E., et al. (2011). Attenuation of brain damage and cognitive impairment by direct renin inhibition in mice with chronic cerebral hypoperfusion. Hypertension 58, 635-642. doi: 10.1161/HYPERTENSIONAHA.111.173534
61. Doubal, F. N., MacLullich, A. M., Ferguson, K. J., Dennis, M. S., and Wardlaw, J. M. (2010). Enlarged perivascular spaces on MRI are a feature of cerebral small vessel disease. Stroke 41, 450-454. doi: 10.1161/STROKEAHA.109.564914
62. Drummond, G. R., Selemidis, S., Griendling, K. K., and Sobey, C. G. (2011). Combating oxidative stress in vascular disease: NADPH oxidases as therapeutic targets. Nat. Rev. Drug Discov. 10, 453-471. doi: 10.1038/nrd3403
63. Dufouil, C., Chalmers, J., Coskun, O., Besancon, V., Bousser, M. G., Guillon, P., et al. (2005). Effects of blood pressure lowering on cerebral white matter hyperintensities in patients with stroke: the PROGRESS (perindopril protection against recurrent stroke study) magnetic resonance imaging substudy. Circulation 112, 1644-1650. doi: 10.1161/CIRCULATIONAHA.104.501163
64. Ebinger, M., Brunecker, P., Schultze-Amberger, J., Gertz, K., Muller, B., Fiebach, J. B., et al. (2012). Statins and cerebral perfusion in patients with leukoaraiosis-a translational proof-of-principal MRI study. Int. J. Stroke 7:E5. doi: 10.1111/j.1747-4949.2012.00807.x
65. Endres, M., Laufs, U., Huang, Z., Nakamura, T., Huang, P., Moskowitz, M. A., et al. (1998). Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase. Proc. Natl. Acad. Sci. U.S.A. 95, 8880-8885. doi: 10.1073/pnas.95.15.8880
66. Erdos, B., Snipes, J. A., Tulbert, C. D., Katakam, P., Miller, A. W., and Busija, D. W. (2006). Rosuvastatin improves cerebrovascular function in Zucker obese rats by inhibiting NAD(P)H oxidase-dependent superoxide production. Am. J. Physiol. Heart Circ. Physiol. 290, H1264-H1270. doi: 10.1152/ajpheart.00804.2005
67. Ergul, A., Li, W., Elgebaly, M. M., Bruno, A., and Fagan, S. C. (2009). Hyperglycemia, diabetes and stroke: focus on the cerebrovasculature. Vascul. Pharmacol. 51, 44-49. doi: 10.1016/j.vph.2009.02.004
68. Esposito, L., Raber, J., Kekonius, L., Yan, F., Yu, G. Q., Bien-Ly, N., et al. (2006). Reduction in mitochondrial superoxide dismutase modulates Alzheimer's disease-like pathology and accelerates the onset of behavioral changes in human amyloid precursor protein transgenic mice. J. Neurosci. 26, 5167-5179. doi: 10.1523/JNEUROSCI.0482-06.2006
69. Estato, V., Obadia, N., Carvalho-Tavares, J., Freitas, F. S., Reis, P., Castro-Faria Neto, H., et al. (2013). Blockade of the renin-angiotensin system improves cerebral microcirculatory perfusion in diabetic hypertensive rats. Microvasc. Res. 87, 41-49. doi: 10.1016/j.mvr.2013.02.007
70. Evgenov, O. V., Pacher, P., Schmidt, P. M., Hasko, G., Schmidt, H. H., and Stasch, J. P. (2006). NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential. Nat. Rev. Drug Discov. 5, 755-768. doi: 10.1038/nrd2038
71. Faber, J. E., Zhang, H., Lassance-Soares, R. M., Prabhakar, P., Najafi, A. H., Burnett, M. S., et al. (2011). Aging causes collateral rarefaction and increased severity of ischemic injury in multiple tissues. Arteriosc. Thromb. Vasc. Biol. 31, 1748-1756. doi: 10.1161/ATVBAHA.111.227314
72. Faraci, F. M. (2011). Protecting against vascular disease in brain. Am. J. Physiol. Heart Circ. Physiol. 300, H1566-H1582. doi: 10.1152/ajpheart.01310.2010
73. Faraci, F. M., Lamping, K. G., Modrick, M. L., Ryan, M. J., Sigmund, C. D., and Didion, S. P. (2006). Cerebral vascular effects of angiotensin II: new insights from genetic models. J. Cereb. Blood Flow Metabol. 26, 449-455. doi: 10.1038/sj.jcbfm.9600204
74. Faraco, G., Moraga, A., Moore, J., Anrather, J., Pickel, V. M., and Iadecola, C. (2013). Circulating endothelin-1 alters critical mechanisms regulating cerebral microcirculation. Hypertension 62, 759-766. doi: 10.1161/HYPERTENSIONAHA.113.01761
75. Gaggini, F., Laleu, B., Orchard, M., Fioraso-Cartier, L., Cagnon, L., Houngninou-Molango, S., et al. (2011). Design, synthesis and biological activity of original pyrazolo-pyrido-diazepine,-pyrazine and-oxazine dione derivatives as novel dual Nox4/Nox1 inhibitors. Bioorg. Med. Chem. 19, 6989-6999. doi: 10.1016/j.bmc.2011.10.016
76. Garcia-Alloza, M., Gregory, J., Kuchibhotla, K. V., Fine, S., Wei, Y., Ayata, C., et al. (2011). Cerebrovascular lesions induce transient beta-amyloid deposition. Brain 134, 3697-3707. doi: 10.1093/brain/awr300
77. Garcia-Alloza, M., Prada, C., Lattarulo, C., Fine, S., Borrelli, L. A., Betensky, R., et al. (2009). Matrix metalloproteinase inhibition reduces oxidative stress associated with cerebral amyloid angiopathy in vivo in transgenic mice. J. Neurochem. 109, 1636-1647. doi: 10.1111/j.1471-4159.2009.06096.x
78. Gianni, D., Taulet, N., Zhang, H., DerMardirossian, C., Kister, J., Martinez, L., et al. (2010). A novel and specific NADPH oxidase-1 (Nox1) small-molecule inhibitor blocks the formation of functional invadopodia in human colon cancer cells. ACS Chem. Biol. 5, 981-993. doi: 10.1021/cb100219n
79. Girouard, H., and Iadecola, C. (2006). Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer disease. J. Appl. Physiol. 100, 328-335. doi: 10.1152/japplphysiol.00966.2005
80. Girouard, H., Park, L., Anrather, J., Zhou, P., and Iadecola, C. (2006). Angiotensin II attenuates endothelium-dependent responses in the cerebral microcirculation through nox-2-derived radicals. Arterioscler. Thromb. Vasc. Biol. 26, 826-832. doi: 10.1161/01.ATV.0000205849.22807.6e
81. Girouard, H., Park, L., Anrather, J., Zhou, P., and Iadecola, C. (2007). Cerebrovascular nitrosative stress mediates neurovascular and endothelial dysfunction induced by angiotensin II. Arterioscler. Thromb. Vasc. Biol. 27, 303-309. doi: 10.1161/01.ATV.0000253885.41509.25
82. Gonzalez-Velasquez, F. J., Kotarek, J. A., and Moss, M. A. (2008). Soluble aggregates of the amyloid-beta protein selectively stimulate permeability in human brain microvascular endothelial monolayers. J. Neurochem. 107, 466-477. doi: 10.1111/j.1471-4159.2008.05618.x
83. Gopalan, Y., Shuaib, I. L., Magosso, E., Ansari, M. A., Abu Bakar, M. R., Wong, J. W., et al. (2014). Clinical investigation of the protective effects of palm vitamin E tocotrienols on brain white matter. Stroke 45, 1422-1428. doi: 10.1161/STROKEAHA.113.004449
84. Gorelick, P. B., Scuteri, A., Black, S. E., DeCarli, C., Greenberg, S. M., Iadecola, C., et al. (2011). Vascular contributions to cognitive impairment and dementia. Stroke 42, 2672-2713. doi: 10.1161/STR.0b013e3182299496
85. Gottesman, R. F., Schneider, A. L., Albert, M., Alonso, A., Bandeen-Roche, K., Coker, L., et al. (2014). Midlife hypertension and 20-year cognitive change: the atherosclerosis risk in communities neurocognitive study. JAMA Neurol. 71, 1218-1227. doi: 10.1001/jamaneurol.2014.1646
86. Haffner, C., Malik, R., and Dichgans, M. (2015). Genetic factors in cerebral small vessel disease and their impact on stroke and dementia. J. Cereb. Blood Flow Metab. doi: 10.1038/jcbfm.2015.71 [Epub ahead of print].
87. Haglund, M., and Englund, E. (2002). Cerebral amyloid angiopathy, white matter lesions and Alzheimer encephalopathy-a histopathological assessment. Dement. Geriatr. Cogn. Disord. 14, 161-166. doi: 10.1159/000063606
88. Hainsworth, A. H., and Markus, H. S. (2008). Do in vivo experimental models reflect human cerebral small vessel disease? A systematic review. J. Cereb. Blood Flow Metabol. 28, 1877-1891. doi: 10.1038/jcbfm.2008.91
89. Hajdu, M. A., Heistad, D. D., Siems, J. E., and Baumbach, G. L. (1990). Effects of aging on mechanics and composition of cerebral arterioles in rats. Circ. Res. 66, 1747-1754. doi: 10.1161/01.RES.66.6.1747
90. Hall, C. B., Verghese, J., Sliwinski, M., Chen, Z., Katz, M., Derby, C., et al. (2005). Dementia incidence may increase more slowly after age 90: results from the Bronx Aging Study. Neurology 65, 882-886. doi: 10.1212/01.wnl.0000176053.98907.3f
91. Hamel, E., Nicolakakis, N., Aboulkassim, T., Ongali, B., and Tong, X. K. (2008). Oxidative stress and cerebrovascular dysfunction in mouse models of Alzheimer's disease. Exp. Physiol. 93, 116-120. doi: 10.1113/expphysiol.2007.038729
92. Han, B. H., Zhou, M. L., Johnson, A. W., Singh, I., Liao, F., Vellimana, A. K., et al. (2015). Contribution of reactive oxygen species to cerebral amyloid angiopathy, vasomotor dysfunction, and microhemorrhage in aged Tg2576 mice. Proc. Natl. Acad. Sci. U.S.A. 112, E881-E890. doi: 10.1073/pnas.1414930112
93. Hartman, R. E., Shah, A., Fagan, A. M., Schwetye, K. E., Parsadanian, M., Schulman, R. N., et al. (2006). Pomegranate juice decreases amyloid load and improves behavior in a mouse model of Alzheimer's disease. Neurobiol. Dis. 24, 506-515. doi: 10.1016/j.nbd.2006.08.006
94. Hartz, A. M., Bauer, B., Soldner, E. L., Wolf, A., Boy, S., Backhaus, R., et al. (2012). Amyloid-beta contributes to blood-brain barrier leakage in transgenic human amyloid precursor protein mice and in humans with cerebral amyloid angiopathy. Stroke 43, 514-523. doi: 10.1161/STROKEAHA.111.627562
95. Hatake, K., Kakishita, E., Wakabayashi, I., Sakiyama, N., and Hishida, S. (1990). Effect of aging on endothelium-dependent vascular relaxation of isolated human basilar artery to thrombin and bradykinin. Stroke 21, 1039-1043. doi: 10.1161/01.STR.21.7.1039
96. Hayashi, T., Hamakawa, K., Nagotani, S., Jin, G., Li, F., Deguchi, K., et al. (2005). HMG CoA reductase inhibitors reduce ischemic brain injury of Wistar rats through decreasing oxidative stress on neurons. Brain Res. 1037, 52-58. doi: 10.1016/j.brainres.2004.12.051
97. Hecquet, C. M., Ahmmed, G. U., Vogel, S. M., and Malik, A. B. (2008). Role of TRPM2 channel in mediating H2O2-induced Ca2+ entry and endothelial hyperpermeability. Circ. Res. 102, 347-355. doi: 10.1161/CIRCRESAHA.107.160176
98. Henning, E. C., Warach, S., and Spatz, M. (2010). Hypertension-induced vascular remodeling contributes to reduced cerebral perfusion and the development of spontaneous stroke in aged SHRSP rats. J. Cereb. Blood Flow Metabol. 30, 827-836. doi: 10.1038/jcbfm.2009.246
99. Iadecola, C., Zhang, F., Niwa, K., Eckman, C., Turner, S. K., Fischer, E., et al. (1999). SOD1 rescues cerebral endothelial dysfunction in mice overexpressing amyloid precursor protein. Nat. Neurosci. 2, 157-161. doi: 10.1038/5715
100. Inzitari, D., Pracucci, G., Poggesi, A., Carlucci, G., Barkhof, F., Chabriat, H., et al. (2009). Changes in white matter as determinant of global functional decline in older independent outpatients: three year follow-up of LADIS (leukoaraiosis and disability) study cohort. BMJ 339:b2477. doi: 10.1136/bmj.b2477
101. Jackman, K., and Iadecola, C. (2014). Neurovascular regulation in the ischemic brain. Antioxid Redox Signal 10, 149-160.
102. Jackman, K. A., Miller, A. A., De Silva, T. M., Crack, P. J., Drummond, G. R., and Sobey, C. G. (2009b). Reduction of cerebral infarct volume by apocynin requires pretreatment and is absent in Nox2-deficient mice. Br. J. Pharmacol. 156, 680-688. doi: 10.1111/j.1476-5381.2008.00073.x
103. Jackman, K. A., Miller, A. A., Drummond, G. R., and Sobey, C. G. (2009a). Importance of NOX1 for angiotensin II-induced cerebrovascular superoxide production and cortical infarct volume following ischemic stroke. Brain Res. 1286, 215-220. doi: 10.1016/j.brainres.2009.06.056
104. Jackson, C. A., Hutchison, A., Dennis, M. S., Wardlaw, J. M., Lindgren, A., Norrving, B., et al. (2010). Differing risk factor profiles of ischemic stroke subtypes: evidence for a distinct lacunar arteriopathy? Stroke 41, 624-629. doi: 10.1161/STROKEAHA.109.558809
105. Jaquet, V., Scapozza, L., Clark, R. A., Krause, K. H., and Lambeth, J. D. (2009). Small-molecule NOX inhibitors: ROS-generating NADPH oxidases as therapeutic targets. Antioxid. Redox Signal. 11, 2535-2552. doi: 10.1089/ARS.2009.2585
106. Jellinger, K. A., and Attems, J. (2010). Prevalence of dementia disorders in the oldest-old: an autopsy study. Acta Neuropathol. 119, 421-433. doi: 10.1007/s00401-010-0654-5
107. Jernigan, N. L., Walker, B. R., and Resta, T. C. (2008). Reactive oxygen species mediate RhoA/Rho kinase-induced Ca2+ sensitization in pulmonary vascular smooth muscle following chronic hypoxia. Am. J. Physiol. Lung. Cell Mol. Physiol. 295, L515-L529. doi: 10.1152/ajplung.00355.2007
108. Jokinen, H., Gouw, A. A., Madureira, S., Ylikoski, R., van Straaten, E. C., van der Flier, W. M., et al. (2011). Incident lacunes influence cognitive decline: the LADIS study. Neurology 76, 1872-1878. doi: 10.1212/WNL.0b013e31821d752f
109. Kahles, T., Luedike, P., Endres, M., Galla, H. J., Steinmetz, H., Busse, R., et al. (2007). NADPH oxidase plays a central role in blood-brain barrier damage in experimental stroke. Stroke 38, 3000-3006. doi: 10.1161/STROKEAHA.107.489765
110. Kalani, A., Pushpakumar, S. B., Vacek, J. C., Tyagi, S. C., and Tyagi, N. (2016). Inhibition of MMP-9 attenuates hypertensive cerebrovascular dysfunction in Dahl salt-sensitive rats. Mol. Cell. Biochem. 413, 25-35. doi: 10.1007/s11010-015-2623-8
111. Kazama, K., Anrather, J., Zhou, P., Girouard, H., Frys, K., Milner, T. A., et al. (2004). Angiotensin II impairs neurovascular coupling in neocortex through NADPH oxidase-derived radicals. Circ. Res. 95, 1019-1026. doi: 10.1161/01.RES.0000148637.85595.c5
112. Kim-Mitsuyama, S., Yamamoto, E., Tanaka, T., Zhan, Y., Izumi, Y., Izumiya, Y., et al. (2005). Critical role of angiotensin II in excess salt-induced brain oxidative stress of stroke-prone spontaneously hypertensive rats. Stroke 36, 1083-1088. doi: 10.1161/01.STR.0000163084.16505.e3
113. Kitayama, J., Faraci, F. M., Lentz, S. R., and Heistad, D. D. (2007). Cerebral vascular dysfunction during hypercholesterolemia. Stroke 38, 2136-2141. doi: 10.1161/STROKEAHA.107.481879
114. Kivipelto, M., Ngandu, T., Laatikainen, T., Winblad, B., Soininen, H., and Tuomilehto, J. (2006). Risk score for the prediction of dementia risk in 20 years among middle aged people: a longitudinal, population-based study. Lancet Neurol. 5, 735-741. doi: 10.1016/S1474-4422(06)70537-3
115. Kleinschnitz, C., Grund, H., Wingler, K., Armitage, M. E., Jones, E., Mittal, M., et al. (2010). Post-stroke inhibition of induced NADPH oxidase type 4 prevents oxidative stress and neurodegeneration. PLoS Biol. 8:479. doi: 10.1371/journal.pbio.1000479
116. Kofler, P. A., Pircher, H., von Grafenstein, S., Diener, T., Holl, M., Liedl, K. R., et al. (2013). Characterisation of Nox4 inhibitors from edible plants. Planta Med. 79, 244-252. doi: 10.1055/s-0032-1328129
117. Kontos, H. A., Wei, E. P., Kukreja, R. C., Ellis, E. F., and Hess, M. L. (1990). Differences in endothelium-dependent cerebral dilation by bradykinin and acetylcholine. Am. J. Physiol. 258, H1261-H1266.
118. Kontos, H. A., Wei, E. P., Povlishock, J. T., and Christman, C. W. (1984). Oxygen radicals mediate the cerebral arteriolar dilation from arachidonate and bradykinin in cats. Circ. Res. 55, 295-303. doi: 10.1161/01.RES.55.3.295
119. Kruyer, A., Soplop, N., Strickland, S., and Norris, E. H. (2015). Chronic hypertension leads to neurodegeneration in the TgSwDI mouse model of Alzheimer's disease. Hypertension 66, 175-182. doi: 10.1161/HYPERTENSIONAHA.115.05524
120. Kuroda, J., Ago, T., Nishimura, A., Nakamura, K., Matsuo, R., Wakisaka, Y., et al. (2014). Nox4 is a major source of superoxide production in human brain pericytes. J. Vasc. Res. 51, 429-438. doi: 10.1159/000369930
121. Laleu, B., Gaggini, F., Orchard, M., Fioraso-Cartier, L., Cagnon, L., Houngninou-Molango, S., et al. (2010). First in class, potent, and orally bioavailable NADPH oxidase isoform 4 (Nox4) inhibitors for the treatment of idiopathic pulmonary fibrosis. J. Med. Chem. 53, 7715-7730. doi: 10.1021/jm100773e
122. Lassegue, B., San Martin, A., and Griendling, K. K. (2012). Biochemistry, physiology, and pathophysiology of NADPH oxidases in the cardiovascular system. Circ. Res. 110, 1364-1390. doi: 10.1161/CIRCRESAHA.111.243972
123. Laufs, U., Endres, M., Stagliano, N., Amin-Hanjani, S., Chui, D. S., Yang, S. X., et al. (2000). Neuroprotection mediated by changes in the endothelial actin cytoskeleton. J. Clin. Invest. 106, 15-24. doi: 10.1172/JCI9639
124. Laufs, U., and Liao, J. K. (1998). Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase. J. Biol. Chem. 273, 24266-24271. doi: 10.1074/jbc.273.37.24266
125. Lee, J. M., Yin, K., Hsin, I., Chen, S., Fryer, J. D., Holtzman, D. M., et al. (2005). Matrix metalloproteinase-9 in cerebral-amyloid-angiopathy-related hemorrhage. J. Neurol. Sci. 229-230, 249-254. doi: 10.1016/j.jns.2004.11.041
126. Li, J., Li, W., Su, J., Liu, W., Altura, B. T., and Altura, B. M. (2003). Hydrogen peroxide induces apoptosis in cerebral vascular smooth muscle cells: possible relation to neurodegenerative diseases and strokes. Brain Res. Bull. 62, 101-106. doi: 10.1016/j.brainresbull.2003.08.011
127. Lynch, C. M., Kinzenbaw, D. A., Chen, X., Zhan, S., Mezzetti, E., Filosa, J., et al. (2013). Nox2-derived superoxide contributes to cerebral vascular dysfunction in diet-induced obesity. Stroke 44, 3195-3201. doi: 10.1161/STROKEAHA.113.001366
128. Maclullich, A. M., Ferguson, K. J., Reid, L. M., Deary, I. J., Starr, J. M., Seckl, J. R., et al. (2009). Higher systolic blood pressure is associated with increased water diffusivity in normal-appearing white matter. Stroke 40, 3869-3871. doi: 10.1161/STROKEAHA.109.547877
129. Marco, S., and Skaper, S. D. (2006). Amyloid beta-peptide1-42 alters tight junction protein distribution and expression in brain microvessel endothelial cells. Neurosci. Lett. 401, 219-224. doi: 10.1016/j.neulet.2006.03.047
130. Mayhan, W. G., Arrick, D. M., Sharpe, G. M., Patel, K. P., and Sun, H. (2006). Inhibition of NAD(P)H oxidase alleviates impaired NOS-dependent responses of pial arterioles in type 1 diabetes mellitus. Microcirculation 13, 567-575. doi: 10.1080/10739680600885194
131. Mayhan, W. G., Arrick, D. M., Sharpe, G. M., and Sun, H. (2008). Age-related alterations in reactivity of cerebral arterioles: role of oxidative stress. Microcirculation 15, 225-236. doi: 10.1080/10739680701641421
132. Mayhan, W. G., Faraci, F. M., Baumbach, G. L., and Heistad, D. D. (1990). Effects of aging on responses of cerebral arterioles. Am. J. Physiol. 258, H1138-H1143.
133. Mayhan, W. G., Simmons, L. K., and Sharpe, G. M. (1991). Mechanism of impaired responses of cerebral arterioles during diabetes mellitus. Am. J. Physiol. 260, H319-H326.
134. McCarthy, D. A., and Macey, M. G. (1996). Novel anticoagulants for flow cytometric analysis of live leucocytes in whole blood. Cytometry 23, 196-204. doi: 10.1002/(SICI)1097-0320(19960301)23:3<196::AID-CYTO3>3.3.CO;2-X
135. Miller, A. A., De Silva, T. M., Judkins, C. P., Diep, H., Drummond, G. R., and Sobey, C. G. (2010). Augmented superoxide production by Nox2-containing NADPH oxidase causes cerebral artery dysfunction during hypercholesterolemia. Stroke 41, 784-789. doi: 10.1161/STROKEAHA.109.575365
136. Miller, A. A., Drummond, G. R., De Silva, T. M., Mast, A. E., Hickey, H., Williams, J. P., et al. (2009). NADPH oxidase activity is higher in cerebral versus systemic arteries of four animal species: role of Nox2. Am. J. Physiol. Heart Circ. Physiol. 296, H220-H225. doi: 10.1152/ajpheart.00987.2008
137. Miller, A. A., Drummond, G. R., Mast, A. E., Schmidt, H. H. H. W., and Sobey, C. G. (2007). Effect of gender on NADPH-oxidase activity, expression, and function in the cerebral circulation: role of estrogen. Stroke 38, 2142-2149. doi: 10.1161/STROKEAHA.106.477406
138. Miller, A. A., Drummond, G. R., Schmidt, H. H., and Sobey, C. G. (2005). NADPH oxidase activity and function are profoundly greater in cerebral versus systemic arteries. Circ. Res. 97, 1055-1062. doi: 10.1161/01.RES.0000189301.10217.87
139. Miller, A. A., Drummond, G. R., and Sobey, C. G. (2006). Novel isoforms of NADPH-oxidase in cerebral vascular control. Pharmacol. Therapeut. 111, 928-948. doi: 10.1016/j.pharmthera.2006.02.005
140. Miller, A. A., Maxwell, K. F., Chrissobolis, S., Bullen, M. L., Ku, J. M., De Silva, T., et al. (2013). Nitroxyl (HNO) suppresses vascular Nox2 oxidase activity. Free Radical Biol. Med. 60, 264-271. doi: 10.1016/j.freeradbiomed.2013.02.025
141. Milner, E., Zhou, M. L., Johnson, A. W., Vellimana, A. K., Greenberg, J. K., Holtzman, D. M., et al. (2014). Cerebral amyloid angiopathy increases susceptibility to infarction after focal cerebral ischemia in Tg2576 mice. Stroke 45, 3064-3069. doi: 10.1161/STROKEAHA.114.006078
142. Modrick, M. L., Didion, S. P., Sigmund, C. D., and Faraci, F. M. (2009). Role of oxidative stress and AT1 receptors in cerebral vascular dysfunction with aging. Am. J. Physiol. Heart Circ. Physiol. 296, H1914-H1919. doi: 10.1152/ajpheart.00300.2009
143. Modrick, M. L., Kinzenbaw, D. A., Chu, Y., Sigmund, C. D., and Faraci, F. M. (2012). Peroxisome proliferator-activated receptor-gamma protects against vascular aging. Am. J. Physiol. Regul. Integr. Comp. Physiol. 302, R1184-R1190. doi: 10.1152/ajpregu.00557.2011
144. Mok, V., and Kim, J. S. (2015). Prevention and management of cerebral small vessel disease. J. Stroke 17, 111-122. doi: 10.5853/jos.2015.17.2.111
145. Mok, V. C., Lam, W. W., Fan, Y. H., Wong, A., Ng, P. W., Tsoi, T. H., et al. (2009). Effects of statins on the progression of cerebral white matter lesion: Post hoc analysis of the ROCAS (regression of cerebral artery stenosis) study. J. Neurol. 256, 750-757. doi: 10.1007/s00415-009-5008-7
146. Moody, D. M., Brown, W. R., Challa, V. R., and Anderson, R. L. (1995). Periventricular venous collagenosis: association with leukoaraiosis. Radiology 194, 469-476. doi: 10.1148/radiology.194.2.7824728
147. Moore, S. M., Zhang, H., Maeda, N., Doerschuk, C. M., and Faber, J. E. (2015). Cardiovascular risk factors cause premature rarefaction of the collateral circulation and greater ischemic tissue injury. Angiogenesis 18, 265-281. doi: 10.1007/s10456-015-9465-6
148. Muller, A., Cadenas, E., Graf, P., and Sies, H. (1984). A novel biologically active seleno-organic compound-I. Glutathione peroxidase-like activity in vitro and antioxidant capacity of PZ 51 (Ebselen). Biochem. Pharmacol. 33, 3235-3239.
149. Munson, J. M., Fried, L., Rowson, S. A., Bonner, M. Y., Karumbaiah, L., Diaz, B., et al. (2012). Anti-invasive adjuvant therapy with imipramine blue enhances chemotherapeutic efficacy against glioma. Sci. Transl. Med. 4:127ra136. doi: 10.1126/scitranslmed.3003016
150. Murad, L. B., Guimaraes, M. R., Paganelli, A., de Oliveira, C. A., and Vianna, L. M. (2014). Alpha-tocopherol in the brain tissue preservation of stroke-prone spontaneously hypertensive rats. J. Physiol. Biochem. 70, 49-60. doi: 10.1007/s13105-013-0279-y
151. Nagasawa, S., Handa, H., Okumura, A., Naruo, Y., Moritake, K., and Hayashi, K. (1979). Mechanical properties of human cerebral arteries. Part 1: effects of age and vascular smooth muscle activation. Surgic. Neurol. 12, 297-304.
152. Nicolakakis, N., Aboulkassim, T., Ongali, B., Lecrux, C., Fernandes, P., Rosa-Neto, P., et al. (2008). 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. 28, 9287-9296. doi: 10.1523/JNEUROSCI.3348-08.2008
153. Niwa, K., Kazama, K., Younkin, S. G., Carlson, G. A., and Iadecola, C. (2002). Alterations in cerebral blood flow and glucose utilization in mice overexpressing the amyloid precursor protein. Neurobiol. Dis. 9, 61-68. doi: 10.1006/nbdi.2001.0460
154. O'Donnell, B. V., Tew, D. G., Jones, O. T., and England, P. J. (1993). Studies on the inhibitory mechanism of iodonium compounds with special reference to neutrophil NADPH oxidase. Biochem. J. 290(Pt 1), 41-49. doi: 10.1042/bj2900041
155. Oldendorf, W. H., Cornford, M. E., and Brown, W. J. (1977). 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. 1, 409-417. doi: 10.1002/ana.410010502
156. Pantoni, L. (2010). Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol. 9, 689-701. doi: 10.1016/S1474-4422(10)70104-6
157. Paravicini, T. M., Chrissobolis, S., Drummond, G. R., and Sobey, C. G. (2004). Increased NADPH-oxidase activity and Nox4 expression during chronic hypertension is associated with enhanced cerebral vasodilatation to NADPH in vivo. Stroke 35, 584-589. doi: 10.1161/01.STR.0000112974.37028.58
158. Paravicini, T. M., Miller, A. A., Drummond, G. R., and Sobey, C. G. (2006). Flow-induced cerebral vasodilatation in vivo involves activation of phosphatidylinositol-3 kinase, NADPH-oxidase, and nitric oxide synthase. J. Cereb. Blood Flow Metabol. 26, 836-845. doi: 10.1038/sj.jcbfm.9600235
159. Park, L., Anrather, J., Girouard, H., Zhou, P., and Iadecola, C. (2007). Nox2-derived reactive oxygen species mediate neurovascular dysregulation in the aging mouse brain. J. Cereb. Blood Flow Metabol. 27, 1908-1918. doi: 10.1038/sj.jcbfm.9600491
160. Park, L., Anrather, J., Zhou, P., Frys, K., Pitstick, R., Younkin, S., et al. (2005). NADPH-oxidase-derived reactive oxygen species mediate the cerebrovascular dysfunction induced by the amyloid beta peptide. J. Neurosci. 25, 1769-1777. doi: 10.1523/JNEUROSCI.5207-04.2005
161. Park, L., Anrather, J., Zhou, P., Frys, K., Wang, G., and Iadecola, C. (2004a). Exogenous NADPH increases cerebral blood flow through NADPH oxidase-dependent and-independent mechanisms. Arterioscler. Thromb. Vasc. Biol. 24, 1860-1865. doi: 10.1161/01.ATV.0000142446.75898.44
162. Park, L., Anrather, J., Forster, C., Kazama, K., Carlson, G. A., and Iadecola, C. (2004b). Abeta-induced vascular oxidative stress and attenuation of functional hyperemia in mouse somatosensory cortex. J. Cereb. Blood Flow Metabol. 24, 334-342. doi: 10.1097/01.WCB.0000105800.49957.1E
163. Park, L., Koizumi, K., El Jamal, S., Zhou, P., Previti, M. L., Van Nostrand, W. E., et al. (2014a). Age-dependent neurovascular dysfunction and damage in a mouse model of cerebral amyloid angiopathy. Stroke 45, 1815-1821. doi: 10.1161/STROKEAHA.114.005179
164. Park, L., Wang, G., Moore, J., Girouard, H., Zhou, P., Anrather, J., et al. (2014b). The key role of transient receptor potential melastatin-2 channels in amyloid-beta-induced neurovascular dysfunction. Nat. Commun. 5:5318. doi: 10.1038/ncomms6318
165. Park, L., Wang, G., Zhou, P., Zhou, J., Pitstick, R., Previti, M. L., et al. (2011). Scavenger receptor CD36 is essential for the cerebrovascular oxidative stress and neurovascular dysfunction induced by amyloid-beta. Proc. Natl. Acad. Sci. U.S.A. 108, 5063-5068. doi: 10.1073/pnas.1015413108
166. Park, L., Zhou, J., Zhou, P., Pistick, R., El Jamal, S., Younkin, L., et al. (2013). Innate immunity receptor CD36 promotes cerebral amyloid angiopathy. Proc. Natl. Acad. Sci. U.S.A. 110, 3089-3094. doi: 10.1073/pnas.1300021110
167. Park, L., Zhou, P., Pitstick, R., Capone, C., Anrather, J., Norris, E. H., et al. (2008). Nox2-derived radicals contribute to neurovascular and behavioral dysfunction in mice overexpressing the amyloid precursor protein. Proc. Natl. Acad. Sci. U.S.A. 105, 1347-1352. doi: 10.1073/pnas.0711568105
168. Pena Silva, R. A., Chu, Y., Miller, J. D., Mitchell, I. J., Penninger, J. M., Faraci, F. M., et al. (2012). Impact of ACE2 deficiency and oxidative stress on cerebrovascular function with aging. Stroke 43, 3358-3363. doi: 10.1161/STROKEAHA.112.667063
169. Perry, B. N., Govindarajan, B., Bhandarkar, S. S., Knaus, U. G., Valo, M., Sturk, C., et al. (2006). Pharmacologic blockade of angiopoietin-2 is efficacious against model hemangiomas in mice. J. Invest. Dermatol. 126, 2316-2322. doi: 10.1038/sj.jid.5700413
170. Perry, H. M. Jr., Davis, B. R., Price, T. R., Applegate, W. B., Fields, W. S., Guralnik, J. M., et al. (2000). Effect of treating isolated systolic hypertension on the risk of developing various types and subtypes of stroke: the Systolic Hypertension in the Elderly Program (SHEP). JAMA 284, 465-471. doi: 10.1001/jama.284.4.465
171. Poels, M. M., Zaccai, K., Verwoert, G. C., Vernooij, M. W., Hofman, A., van der Lugt, A., et al. (2012). Arterial stiffness and cerebral small vessel disease: the Rotterdam Scan Study. Stroke 43, 2637-2642. doi: 10.1161/STROKEAHA.112.676528
172. Poggesi, A., Pasi, M., Pescini, F., Pantoni, L., and Inzitari, D. (2015). Circulating biologic markers of endothelial dysfunction in cerebral small vessel disease: a review. J. Cereb. Blood Flow Metab. doi: 10.1038/jcbfm.2015.116 [Epub ahead of print].
173. Potter, G. M., Doubal, F. N., Jackson, C. A., Chappell, F. M., Sudlow, C. L., Dennis, M. S., et al. (2015). Enlarged perivascular spaces and cerebral small vessel disease. Int. J. Stroke 10, 376-381. doi: 10.1111/ijs.12054
174. Potter, G. M., Doubal, F. N., Jackson, C. A., Sudlow, C. L., Dennis, M. S., and Wardlaw, J. M. (2012). Lack of association of white matter lesions with ipsilateral carotid artery stenosis. Cerebrovasc. Dis. 33, 378-384. doi: 10.1159/000336762
175. Pretnar-Oblak, J., Sabovic, M., Sebestjen, M., Pogacnik, T., and Zaletel, M. (2006). Influence of atorvastatin treatment on L-arginine cerebrovascular reactivity and flow-mediated dilatation in patients with lacunar infarctions. Stroke 37, 2540-2545. doi: 10.1161/01.STR.0000239659.99112.fb
176. Pretnar-Oblak, J., Sebestjen, M., and Sabovic, M. (2008). Statin treatment improves cerebral more than systemic endothelial dysfunction in patients with arterial hypertension. Am. J. Hypertens. 21, 674-678. doi: 10.1038/ajh.2008.153
177. Raz, L., Zhang, Q. G., Zhou, C. F., Han, D., Gulati, P., Yang, L. C., et al. (2010). Role of Rac1 GTPase in NADPH oxidase activation and cognitive impairment following cerebral ischemia in the rat. PLoS ONE 5:e12606. doi: 10.1371/journal.pone.0012606
178. Rey, F. E., Cifuentes, M. E., Kiarash, A., Quinn, M. T., and Pagano, P. J. (2001). Novel competitive inhibitor of NAD(P)H oxidase assembly attenuates vascular O(2)(-) and systolic blood pressure in mice. Circ. Res. 89, 408-414. doi: 10.1161/hh1701.096037
179. Rost, N. S., Rahman, R. M., Biffi, A., Smith, E. E., Kanakis, A., Fitzpatrick, K., et al. (2010). White matter hyperintensity volume is increased in small vessel stroke subtypes. Neurology 75, 1670-1677. doi: 10.1212/WNL.0b013e3181fc279a
180. Ruzali, W. A., Kehoe, P. G., and Love, S. (2013). Influence of LRP-1 and apolipoprotein E on amyloid-beta uptake and toxicity to cerebrovascular smooth muscle cells. J. Alzheimer's Dis. 33, 95-110. doi: 10.3233/JAD-2012-121336
181. Sander, K., Hof, U., Poppert, H., Conrad, B., and Sander, D. (2005). Improved cerebral vasoreactivity after statin administration in healthy adults. J. Neuroimag. 15, 266-270. doi: 10.1111/j.1552-6569.2005.tb00320.x
182. Santhanam, A. V., d'Uscio, L. V., and Katusic, Z. S. (2014). Erythropoietin increases bioavailability of tetrahydrobiopterin and protects cerebral microvasculature against oxidative stress induced by eNOS uncoupling. J. Neurochem. 131, 521-529. doi: 10.1111/jnc.12824
183. Santhanam, A. V. R., d'Uscio, L. V., Smith, L. A., and Katusic, Z. S. (2012). Uncoupling of eNOS causes superoxide anion production and impairs NO signaling in the cerebral microvessels of hph-1 mice. J. Neurochem. 122, 1211-1218. doi: 10.1111/j.1471-4159.2012.07872.x
184. Selemidis, S., Sobey, C. G., Wingler, K., Schmidt, H. H., and Drummond, G. R. (2008). NADPH oxidases in the vasculature: molecular features, roles in disease and pharmacological inhibition. Pharmacol. Therapeut. 120, 254-291. doi: 10.1016/j.pharmthera.2008.08.005
185. Shen, J., Bai, X. Y., Qin, Y., Jin, W. W., Zhou, J. Y., Zhou, J. P., et al. (2011). Interrupted reperfusion reduces the activation of NADPH oxidase after cerebral I/R injury. Free Radical Biol. Med. 50, 1780-1786. doi: 10.1016/j.freeradbiomed.2011.03.028
186. Silberberg, D. H., Manning, M. C., and Schreiber, A. D. (1984). Tissue culture demyelination by normal human serum. Ann. Neurol. 15, 575-580. doi: 10.1002/ana.410150610
187. Smith, E. E., Vijayappa, M., Lima, F., Delgado, P., Wendell, L., Rosand, J., et al. (2008). Impaired visual evoked flow velocity response in cerebral amyloid angiopathy. Neurology 71, 1424-1430. doi: 10.1212/01.wnl.0000327887.64299.a4
188. Stielow, C., Catar, R. A., Muller, G., Wingler, K., Scheurer, P., Schmidt, H. H., et al. (2006). Novel Nox inhibitor of oxLDL-induced reactive oxygen species formation in human endothelial cells. Biochem. Biophys. Res. Commun. 344, 200-205. doi: 10.1016/j.bbrc.2006.03.114
189. Stolk, J., Hiltermann, T. J., Dijkman, J. H., and Verhoeven, A. J. (1994). Characteristics of the inhibition of NADPH oxidase activation in neutrophils by apocynin, a methoxy-substituted catechol. Am. J. Respir. Cell Mol. Biol. 11, 95-102. doi: 10.1165/ajrcmb.11.1.8018341
190. Study Collaborative, G. (2002). MRC/BHF heart protection study of antioxidant vitamin supplementation in 20, 536 high-risk individuals: a randomised placebo-controlled trial. Lancet 360, 23-33. doi: 10.1016/S0140-6736(02)09328-5
191. Stuehr, D. J., Fasehun, O. A., Kwon, N. S., Gross, S. S., Gonzalez, J. A., Levi, R., et al. (1991). Inhibition of macrophage and endothelial cell nitric oxide synthase by diphenyleneiodonium and its analogs. FASEB 5, 98-103.
192. Sun, Q. A., Hess, D. T., Wang, B., Miyagi, M., and Stamler, J. S. (2012). Off-target thiol alkylation by the NADPH oxidase inhibitor 3-benzyl-7-(2-benzoxazolyl)thio-1, 2, 3-triazolo[4, 5-d]pyrimidine (VAS2870). Free Radical Biol. Med. 52, 1897-1902. doi: 10.1016/j.freeradbiomed.2012.02.046
193. Taheri, S., Gasparovic, C., Huisa, B. N., Adair, J. C., Edmonds, E., Prestopnik, J., et al. (2011). Blood-brain barrier permeability abnormalities in vascular cognitive impairment. Stroke 42, 2158-2163. doi: 10.1161/STROKEAHA.110.611731
194. Tanaka, N., Katayama, Y., Katsumata, T., Otori, T., and Nishiyama, Y. (2007). Effects of long-term administration of HMG-CoA reductase inhibitor, atorvastatin, on stroke events and local cerebral blood flow in stroke-prone spontaneously hypertensive rats. Brain Res. 1169, 125-132. doi: 10.1016/j.brainres.2007.07.012
195. Tang, X. N., Cairns, B., Cairns, N., and Yenari, M. A. (2008). Apocynin improves outcome in experimental stroke with a narrow dose range. Neuroscience 154, 556-562. doi: 10.1016/j.neuroscience.2008.03.090
196. ten Dam, V. H., van den Heuvel, D. M., van Buchem, M. A., Westendorp, R. G., Bollen, E. L., Ford, I., et al. (2005). Effect of pravastatin on cerebral infarcts and white matter lesions. Neurology 64, 1807-1809. doi: 10.1212/01.WNL.0000161844.00797.73
197. ten Freyhaus, H., Huntgeburth, M., Wingler, K., Schnitker, J., Baumer, A. T., Vantler, M., et al. (2006). Novel Nox inhibitor VAS2870 attenuates PDGF-dependent smooth muscle cell chemotaxis, but not proliferation. Cardiovasc. Res 71, 331-341. doi: 10.1016/j.cardiores.2006.01.022
198. Tong, X. K., Nicolakakis, N., Fernandes, P., Ongali, B., Brouillette, J., Quirion, R., et al. (2009). Simvastatin improves cerebrovascular function and counters soluble amyloid-beta, inflammation and oxidative stress in aged APP mice. Neurobiol. Dis. 35, 406-414. doi: 10.1016/j.nbd.2009.06.003
199. Toyama, K., Koibuchi, N., Uekawa, K., Hasegawa, Y., Kataoka, K., Katayama, T., et al. (2014). Apoptosis signal-regulating kinase 1 is a novel target molecule for cognitive impairment induced by chronic cerebral hypoperfusion. Arterioscler. Thromb. Vasc. Biol. 34, 616-625. doi: 10.1161/ATVBAHA.113.302440
200. Ueno, Y., Koike, M., Shimada, Y., Shimura, H., Hira, K., Tanaka, R., et al. (2015). L-carnitine enhances axonal plasticity and improves white-matter lesions after chronic hypoperfusion in rat brain. J. Cereb. Blood Flow Metabol. 35, 382-391. doi: 10.1038/jcbfm.2014.210
201. Umesalma, S., Houwen, F. K., Baumbach, G. L., and Chan, S. L. (2016). Roles of caveolin-1 in angiotensin ii-induced hypertrophy and inward remodeling of cerebral pial arterioles. Hypertension 67, 623-629. doi: 10.1161/HYPERTENSIONAHA.115.06565
202. van der Flier, W. M., van Straaten, E. C., Barkhof, F., Verdelho, A., Madureira, S., Pantoni, L., et al. (2005). Small vessel disease and general cognitive function in nondisabled elderly: the LADIS study. Stroke 36, 2116-2120. doi: 10.1161/01.STR.0000179092.59909.42
203. van Horssen, J., de Jong, D., de Waal, R. M., Maass, C., Otte-Holler, I., Kremer, B., et al. (2005). Cerebral amyloid angiopathy with severe secondary vascular pathology: a histopathological study. Dement. Geriatr. Cogn. Disord. 20, 321-330. doi: 10.1159/000088462
204. Vejrazka, M., Micek, R., and Stipek, S. (2005). Apocynin inhibits NADPH oxidase in phagocytes but stimulates ROS production in non-phagocytic cells. Biochim. Biophys. Acta 1722, 143-147. doi: 10.1016/j.bbagen.2004.12.008
205. Verbeek, M. M., de Waal, R. M., Schipper, J. J., and Van Nostrand, W. E. (1997). Rapid degeneration of cultured human brain pericytes by amyloid beta protein. J. Neurochem. 68, 1135-1141. doi: 10.1046/j.1471-4159.1997.68031135.x
206. Vermeer, S. E., Longstreth, W. T., and Koudstaal, P. J. (2007). Silent brain infarcts: a systematic review. Lancet Neurol. 6, 611-619. doi: 10.1016/S1474-4422(07)70170-9
207. Walder, C. E., Green, S. P., Darbonne, W. C., Mathias, J., Rae, J., Dinauer, M. C., et al. (1997). Ischemic stroke injury is reduced in mice lacking a functional NADPH oxidase. Stroke 28, 2252-2258. doi: 10.1161/01.STR.28.11.2252
208. Wang, M., Takagi, G., Asai, K., Resuello, R. G., Natividad, F. F., Vatner, D. E., et al. (2003). Aging increases aortic MMP-2 activity and angiotensin II in nonhuman primates. Hypertension 41, 1308-1316. doi: 10.1161/01.HYP.0000073843.56046.45
209. Wang, M., Zhang, J., Jiang, L. Q., Spinetti, G., Pintus, G., Monticone, R., et al. (2007). Proinflammatory profile within the grossly normal aged human aortic wall. Hypertension 50, 219-227. doi: 10.1161/HYPERTENSIONAHA.107.089409
210. Wardlaw, J. M., Dennis, M. S., Warlow, C. P., and Sandercock, P. A. (2001). Imaging appearance of the symptomatic perforating artery in patients with lacunar infarction: occlusion or other vascular pathology? Ann. Neurol. 50, 208-215. doi: 10.1002/ana.1082
211. Wardlaw, J. M., Smith, C., and Dichgans, M. (2013). Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging. Lancet Neurol. 12, 483-497. doi: 10.1016/S1474-4422(13)70060-7
212. Witting, P. K., Upston, J. M., and Stocker, R. (1997). Role of alpha-tocopheroxyl radical in the initiation of lipid peroxidation in human low-density lipoprotein exposed to horse radish peroxidase. Biochemistry 36, 1251-1258. doi: 10.1021/bi962493j
213. Witting, P. K., Willhite, C. A., Davies, M. J., and Stocker, R. (1999). Lipid oxidation in human low-density lipoprotein induced by metmyoglobin/H2O2: involvement of alpha-tocopheroxyl and phosphatidylcholine alkoxyl radicals. Chem. Res. Toxicol. 12, 1173-1181. doi: 10.1021/tx9900472
214. Xie, H., Ray, P. E., and Short, B. L. (2005). NF-kappaB activation plays a role in superoxide-mediated cerebral endothelial dysfunction after hypoxia/reoxygenation. Stroke 36, 1047-1052. doi: 10.1161/01.STR.0000157664.34308.cc
215. Xiong, Y., Wong, A., Cavalieri, M., Schmidt, R., Chu, W. W., Liu, X., et al. (2014). Prestroke statins, progression of white matter hyperintensities, and cognitive decline in stroke patients with confluent white matter hyperintensities. Neurotherapeutics 11, 606-611. doi: 10.1007/s13311-014-0270-5
216. Xu, W. H. (2014). Large artery: an important target for cerebral small vessel diseases. Ann. Transl. Med. 2:78. doi: 10.3978/j.issn.2305-5839.2014.08.10
217. Xu, Y., Zhang, J. J., Xiong, L., Zhang, L., Sun, D., and Liu, H. (2010). Green tea polyphenols inhibit cognitive impairment induced by chronic cerebral hypoperfusion via modulating oxidative stress. J. Nutr. Biochem. 21, 741-748. doi: 10.1016/j.jnutbio.2009.05.002
218. Yamaguchi, T., Sano, K., Takakura, K., Saito, I., Shinohara, Y., Asano, T., et al. (1998). Ebselen in acute ischemic stroke: a placebo-controlled, double-blind clinical trial. Ebselen Study Group. Stroke 29, 12-17. doi: 10.1161/01.STR.29.1.12
219. Yamamoto, E., Tamamaki, N., Nakamura, T., Kataoka, K., Tokutomi, Y., Dong, Y. F., et al. (2008). Excess salt causes cerebral neuronal apoptosis and inflammation in stroke-prone hypertensive rats through angiotensin II-induced NADPH oxidase activation. Stroke 39, 3049-3056. doi: 10.1161/STROKEAHA.108.517284
220. Yoshioka, H., Niizuma, K., Katsu, M., Okami, N., Sakata, H., Kim, G. S., et al. (2011). NADPH oxidase mediates striatal neuronal injury after transient global cerebral ischemia. J. Cereb. Blood Flow Metabol. 31, 868-880. doi: 10.1038/jcbfm.2010.166
221. Zang, M., Xu, S., Maitland-Toolan, K. A., Zuccollo, A., Hou, X., Jiang, B., et al. (2006). Polyphenols stimulate AMP-activated protein kinase, lower lipids, and inhibit accelerated atherosclerosis in diabetic LDL receptor-deficient mice. Diabetes Metab. Res. Rev. 55, 2180-2191.
222. Zembowicz, A., Hatchett, R. J., Radziszewski, W., and Gryglewski, R. J. (1993). Inhibition of endothelial nitric oxide synthase by ebselen. Prevention by thiols suggests the inactivation by ebselen of a critical thiol essential for the catalytic activity of nitric oxide synthase. J. Pharmacol. Exp. Therapeut. 267, 1112-1118.
223. Zhang, H. F., Li, T. B., Liu, B., Lou, Z., Zhang, J. J., Peng, J. J., et al. (2015). Inhibition of myosin light chain kinase reduces NADPH oxidase-mediated oxidative injury in rat brain following cerebral ischemia/reperfusion. Naunyn Schmied. Arch. Pharmacol. 388, 953-963. doi: 10.1007/s00210-015-1125-2
224. Zhang, M., Mao, Y., Ramirez, S. H., Tuma, R. F., and Chabrashvili, T. (2010). Angiotensin II induced cerebral microvascular inflammation and increased blood-brain barrier permeability via oxidative stress. Neuroscience 171, 852-858. doi: 10.1016/j.neuroscience.2010.09.029