1. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol 2010;9:689–701.
2. , , , Heterogeneity in the penumbra. J Cereb Blood Flow Metab 2011;31:1836–1851.
3. The neurovascular unit in the setting of stroke. J Intern Med 2010;267:156–171.
4. The vascular system of the cerebral cortex. Adv Anat Embryol Cell Biol 1980;59:1–62.
5. Morphometric evaluation of capillaries in different laminae of rat cerebral cortex by automatic image analysis: changes during development and aging. In , ed. Advances in Neurology, 20th edn. New York, NY: Raven Press; 1978: pp. 1–9.
6. Patterns of vascularization in the developing cerebral cortex. In and , eds. Ciba Foundation Symposium 100 – Development of the Vascular System. Chichester, UK: John Wiley and Sons; 2008: pp. 20–36.
7. , , , , Focal cerebral ischemia preferentially affects neurons distant from their neighboring microvessels. J Cereb Blood Flow Metab 2005;25:257–266.
8. , , , et al. Functional variations in parenchymal microvascular systems within the brain. Magn Reson Med 1991;19:217–220.
9. Ischemic penumbra: evidence from functional imaging in man. J Cereb Blood Flow Metab 2000;20:1276–1293.
10. Experimental evidence of ischemic thresholds and functional recovery. Stroke 1992;23:1668–1672.
11. , , , et al. Dynamic penumbra demonstrated by sequential multitracer PET after middle cerebral artery occlusion in cats. J Cereb Blood Flow Metab 1994;14:892–902.
12. . The Cerebral Infarct: Pathology, Pathogenesis, and Computed Tomography. Berlin: Springer-Verlag; 1985: pp. 4–5.
13. , , General and comparative anatomy of the cerebral circulation. In , , , eds. Cerebral Blood Flow and Metabolism. New York, NY: Raven Press; 1993: pp. 3–39.
14. , , Cerebral Blood Flow and Metabolism. New York, NY: Raven Press; 1993.
15. , , , Generation of an environmental niche for neural stem cell development by the extracellular matrix molecule tenascin C. Development 2004;131:3423–3432.
16. Inflammation and the neurovascular unit in the setting of focal cerebral ischemia. Neuroscience 2009;158:972–982.
17. The neurovascular unit, matrix proteases, and innate inflammation. Ann NY Acad Sci 2010;1207:46–49.
18. Toward the neurovascular unit: a journey in clinical translation. 2012 Thomas Willis lecture. Stroke 2013;44:263–269.
19. , , , et al. Human cerebromicrovascular endothelium: studies in vitro. J Cereb Blood Flow Metab 1989;9:S393.
20. , , , Cerebral microvessels as mediators of cerebral transport. Adv Neurol 1978;20:189–196.
21. , , , , The ischemic and postischemic effect on the uptake of neutral amino acids in isolated cerebral capillaries. Experientia 1993;15:625–626.
22. , , , Cerebrovascular endothelium in vitro: studies related to blood–brain barrier function. Proceedings of the XIst International Congress of Neuropathy 1991;(Suppl. 4):785–787.
23. , , Endothelial cell heterogeneity of blood–brain barrier gene expression along the cerebral microvasculature. J Neurosci Res 2010;88:1457–1474.
24. , , , , Distribution of integrin-like immunoreactivity on primate brain microvasculature. J Neuropathol Exp Neurol 1996;55:236–245.
25. , , , , The rapid decrease in astrocyte-associated dystroglycan expression by focal cerebral ischemia is protease-dependent. J Cereb Blood Flow Metab 2008;28:812–823.
26. , , , et al. Responses of endothelial cell and astrocyte matrix-integrin receptors to ischemia mimic those observed in the neurovascular unit. Stroke 2008;39:191–197.
27. , Integrin–matrix interactions in the cerebral microvasculature. Arterioscler Thromb Vasc Biol 2006;26:1966–1975.
28. , The blood–brain barrier/neurovascular unit in health and disease. Pharmacol Rev 2005;57:173–185.
29. , , , et al. Interendothelial claudin-5 expression depends upon cerebral endothelial cell–matrix adhesion by β1-integrins. J Cereb Blood Flow Metab 2011;31:1972–1985.
30. , , The role of adherens junctions and VE-cadherin in the control of vascular permeability. J Cell Sci 2008;121:2115–2122.
31. Introduction to the Blood–Brain Barrier. Methodology, Biology and Pathology. Cambridge: Cambridge University Press; 1998.
32. , , , et al. P-selectin and intercellular adhesion molecule-1 expression after focal brain ischemia and reperfusion. Stroke 1994;25:202–211.
33. , , , , E-selectin appears in non-ischemic tissue during experimental focal cerebral ischemia. Stroke 1996;27:1386–1392.
34. , , , Astrocytes secrete basal lamina after hemisection of rat spinal cord. Brain Res 1985;327:135–141.
35. , , , Human fetal astrocytes induce the expression of blood–brain barrier specific proteins by autologous endothelial cells. Brain Res 1993;625:238–243.
36. , , , , Comparison of gene expression of extracellular matrix molecules in brain microvascular endothelial cells and astrocytes. Biochem Biophys Res Commun 1992;189:877–884.
37. , , , , Thrombin stimulates synthesis of type IV collagen and tissue inhibitor of metalloproteinase-1 by cultured human mesangial cells. J Am Soc Nephrol 1999;10:1516–1523.
38. , , , et al. Astrocyte-mediated control of cerebral blood flow. Nat Neurosci 2006;9:260–267.
39. , , , Astrocytic complexity distinguishes the human brain. Trends Neurosci 2006;29:547–553.
40. , Astrocytes in cerebral ischemic injury: morphological and general considerations. GLIA 2005;50:287–298.
41. , Astrocyte-mediated control of cerebral microcirculation. Trends Neurosci 2003;26:340–344.
42. , , , , Rapid disruption of an astrocyte interaction with the extracellular matrix mediated by integrin α6β4 during focal cerebral ischemia/reperfusion. Stroke 1997;28:858–865.
43. , , Astrocytes and the regulation of cerebral blood flow. Trends Neurosci 2009;32:160–169.
44. , Control of brain capillary blood flow. J Cereb Blood Flow Metab 2012;32:1167–1176.
45. , The neurobiology of glia in the context of water and ion homeostasis. Neuroscience 2004;129:877–896.
46. , , , Disruption of dystroglycan–laminin interactions modulates water uptake by astrocytes. Brain Res 2013.
47. , , , CNS microvascular pericytes exhibit multipotential stem cell activity. J Cereb Blood Flow Metab 2006;26:613–624.
48. , , , Bidirectional control of CNS capillary diameter by pericytes. Nature 2006;443:700–704.
49. , , Pericyte–endothelial cell interaction increases MMP-9 secretion at the blood–brain barrier in vitro. Brain Res 2008;1189:1–11.
50. , , , Regulation of the blood–brain barrier integrity by pericytes via matrix metalloproteinases mediated activation of vascular endothelial growth factor in vitro. Brain Res 2010;1347:1–10.
51. Pericyte signaling in the neurovascular unit. Stroke 2009;40:S13–S15.
52. , , , Mast cells in the brain: evidence and functional significance. Trends Neurosci 1996;19:25–31.
53. , , , , An emerging role of mast cells in cerebral ischemia and hemorrhage. Ann Med 2009;41:438–450.
54. , , , Cerebral mast cells regulate early ischemic brain swelling and neutrophil accumulation. J Cereb Blood Flow Metab 2006;26:605–612.
55. , , , Mast cell blocking reduces brain edema and hematoma volume and improves outcome after experimental intracerebral hemorrhage. J Cereb Blood Flow Metab 2007;27:795–802.
56. , , , et al. A key role for mast cell chymase in the activation of pro-matrix metalloprotease-9 and pro-matrix metalloprotease-2. J Biol Chem 2005;280:9291–9296.
57. , , Pericellular substrates of human mast cell tryptase: 72 000 dalton gelatinase and fibronectin. J Cell Biochem 1992;50:337–349.
58. , , , , Serafini B. Intracerebral regulation of immune responses. Ann Med 2001;33:510–515.
59. Immune function of microglia. GLIA 2001;36:165–179.
60. , , , et al. Contribution of microglia/macrophages to expansion of infarction and response of oligodendrocytes after focal cerebral ischemia in rats. Stroke 2000;31:1735–1743.
61. , , , et al. Matrix metalloproteinases increase very early during experimental focal cerebral ischemia. J Cereb Blood Flow Metab 1999;19:624–633.
62. , , , et al. Focal cerebral ischemia induces active proteases that degrade microvascular matrix. Stroke 2004;35:998–1004.
63. , , , et al. Activation systems for latent matrix metalloproteinase-2 are upregulated immediately after focal cerebral ischemia. J Cereb Blood Flow Metab 2003;23:1408–1419.
64. , Fine structural localization of a blood–brain barrier to exogenous peroxidase. J Cell Biol 1967;34:207–217.
65. Regulation of P-glycoprotein and other ABC drug transporters at the blood–brain barrier. Trends Pharmacol Sci 2010;31:246–254.
66. , Developing nervous tissue induces formation of blood–brain barrier characteristics in invading endothelial cells: a study using quail–chicken transplantation chimeras. Dev Biol 1981;84:183–192.
67. , , , , Reversible disruption of tight junction complexes in the rat blood–brain barrier, following transitory focal astrocyte loss. GLIA 2004;48:1–13.
68. , , Closing the gap between the in-vivo and in-vitro blood–brain barrier tightness. Brain Res 2009;1284:12–21.
69. , , Dziegielewska KM. Barriers in the immature brain. Cell Mol Neurobiol 2000;20:29–40.
70. , , , Pericytes are required for blood–brain barrier integrity during embryogenesis. Nature 2010;468:562–566.
71. , , Brain microvessels are innervated by locus ceruleus noradrenergic neurons. Neurosci Lett 1989;97:203–208.
72. , , , et al. Degeneration of noradrenergic fibres from the locus coeruleus causes tight-junction disorganisation in the rat brain. Eur J Neurosci 2006;24:3393–3400.
73. , , , et al. Blood–brain barrier opened by stimulation of the parasympathetic sphenopalatine ganglion: a new method for macromolecule delivery to the brain. J Neurosurg 2004;101:303–309.
74. Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat Rev Neurosci 2004;5:347–360.
75. Stroke and neurovascular protection. N Engl J Med 2006;354:553–555.
76. , Glial regulation of the cerebral microvasculature. Nat Neurosci 2007;10:1369–1376.
77. , , , , Polymorphonuclear leukocytes occlude capillaries following middle cerebral artery occlusion and reperfusion in baboons. Stroke 1991;22:1276–1283.
78. , , , , Fibrin contributes to microvascular obstructions and parenchymal changes during early focal cerebral ischemia and reperfusion. Stroke 1994;25:1847–1853.
79. , , , et al. DNA scission after focal brain ischemia. Temporal differences in two species. Stroke 1997;28:1245–1254.
80. , Light and electron-microscopic features of brain ischemia. In , ed. Cerebral Blood Flow. Physiologic and Clinical Aspects. New York, NY: McGraw-Hill; 1987: pp. 75–91.
81. , , , et al. Brain capillaries expand and rupture in areas of ischemia and reperfusion. In , , eds. Cerebrovascular Diseases. New York, NY: Raven Press; 1983: pp. 169–182.
82. , , , Ultrastructural and temporal changes of the microvascular basement membrane and astrocyte interface following focal cerebral ischemia. J Neurosci Res 2009;87:668–676.
83. , , Free radicals as triggers of brain edema formation after stroke. Free Radic Biol Med 2005;39:51–70.
84. , , , Microvascular basal lamina antigens disappear during cerebral ischemia and reperfusion. Stroke 1995;26:2120–2126.
85. , , Hemorrhagic transformation and microvascular integrity during focal cerebral ischemia/reperfusion. J Cereb Blood Flow Metab 1996;16:1373–1378.
86. , , , et al. Influx of leukocytes and platelets in an evolving brain infarct (Wistar rat). Am J Pathol 1994;144:188–199.
87. , , , et al. Concomitant cortical expression of TNF-α and IL-1β mRNA following transient focal ischemia. Mol Chem Neuropathol 1994;23:103–114.
88. , , An experimental model of the Krogh tissue cylinder: two dimensional quantitation of the oxygen gradient. Adv Exp Med Biol 1977;94:127–136.
89. . Relationship of neurovascular elements to neuron injury during ischemia. Cerebrovasc Dis 2009;27(Suppl 1):65–76.
90. , , , et al. Rapid loss of microvascular integrin expression during focal brain ischemia reflects neuron injury. J Cereb Blood Flow Metab 2001;21:835–846.
91. , , , et al. Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood–brain barrier and white matter components after cerebral ischemia. J Neurosci 2001;21:7724–7732.
92. , , , et al. Activated protein C inhibits tissue plasminogen activator-induced brain hemorrhage. Nat Med 2006;12:1278–1285.
93. , , , et al. Dissociation and protection of the neurovascular unit after thrombolysis and reperfusion in ischemic rat brain. J Cereb Blood Flow Metab 2009;29:715–725.
94. , , , et al. Blood–brain barrier disruption in humans is independently associated with increased matrix metalloproteinase-9. Stroke 2010;41:e123–e128.
95. , , , et al. Matrix metalloproteinase expression is related to hemorrhagic transformation after cardioembolic stroke. Stroke 2001;32:2762–2667.
96. , , , et al. Microglial activation and matrix protease generation during focal cerebral ischemia. Stroke 2007;38:646–651.
97. , , , et al. Microglial cell activation is a source of metalloproteinase generation during hemorrhagic transformation. J Cereb Blood Flow Metab 2012;32:919–932.
98. , , , , Tight junctions at the blood brain barrier: physiological architecture and disease-associated dysregulation. Fluids Barriers CNS 2012;9:23.
99. Neurogenic control of the cerebral microcirculation: is dopamine minding the store? Nat Neurosci 1998;1:263–265.
100. , , , Central noradrenergic regulation of cerebral blood flow and vascular permeability. Proc Natl Acad Sci USA 1975;72:3726–3730.
101. , , , et al. Experimental acute thrombotic stroke in baboons. Stroke 1986;17:1254–1265.
102. , , , et al. Molecular mechanisms of ischemic cerebral edema: role of electroneutral ion transport. Physiology (Bethesda) 2009;24:257–265.
103. , , , et al. Recombinant tissue plasminogen activator in acute thrombotic and embolic stroke. Ann Neurol 1992;32:78–86.
104. Bleeding in the brain: amyloid-β may keep clots away. Nat Med 2009;15:1132–1133.
105. , , , , Induction of MMP-9 expression and endothelial injury by oxidative stress after spinal cord injury. J Neurotrauma 2008;25:184–195.
106. , , Trimethyltin induces gelatinase B and urokinase in rat brain. Neurosci Lett 1997;228:147–150.
107. , , , et al. Hemoglobin-induced oxidative stress contributes to matrix metalloproteinase activation and blood–brain barrier dysfunction in vivo. J Cereb Blood Flow Metab 2010;30:1939–1950.
108. , , , , Delayed matrix metalloproteinase inhibition reduces intracerebral hemorrhage after embolic stroke in rats. Exp Neurol 2008;213:196–201.
109. , , , Influence of hyperglycemia on oxidative stress and matrix metalloproteinase-9 activation after focal cerebral ischemia/reperfusion in rats: relation to blood–brain barrier dysfunction. Stroke 2007;38:1044–1049.
110. , Divergent role for MMP-2 in myelin breakdown and oligodendrocyte death following transient global ischemia. J Neurosci Res 2010;88:764–773.
111. , , , et al. Matrix metalloproteinase-9 concentration after spontaneous intracerebral hemorrhage. J Neurosurg 2003;99:65–70.
112. , , , et al. Increased brain expression of matrix metalloproteinase-9 after ischemic and hemorrhagic human stroke. Stroke 2006;37:1399–1406.
113. , , , et al. Matrix metalloproteinase-9 pretreatment level predicts intracranial hemorrhagic complications after thrombolysis in human stroke. Circulation 2003;107:598–603.
114. , , , , Cerebral ischemia. II. The no-reflow phenomenon. Am J Pathol 1968;52:437–453.
115. , , Restoration of middle cerebral artery flow in experimental infarction. J Neurosurg 1969;31:311–322.
116. , , , , Inhibition of polymorphonuclear leukocyte adherence suppresses no-reflow after focal cerebral ischemia in baboons. Stroke 1992;23:712–718.
117. , , , et al. Tissue factor contributes to microvascular defects following cerebral ischemia. Stroke 1993;24:847–853.
118. , , , et al. Integrin α(IIb)β(3) inhibitor preserves microvascular patency in experimental acute focal cerebral ischemia. Stroke 2000;31:1402–1410.
119. , , , et al. Anti-thrombotic activity of RG13965, a novel platelet fibrinogen receptor antagonist. Thromb Res 1996;82:495–507.
120. Blood–brain barrier and cerebral small vessel disease. J Neurol Sci 2010;299:66–71.
121. , , , et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560–2572.