Skip to main content
SpringerLink
Log in

Cells of the Blood–Brain Barrier: An Overview of the Neurovascular Unit in Health and Disease

  • Protocol
  • First Online:
The Blood-Brain Barrier

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2492))

Abstract

The brain is endowed with highly specialized vasculature that is both structurally and functionally unique compared to vasculature supplying peripheral organs. The blood–brain barrier (BBB) is formed by endothelial cells of the cerebral vasculature and prevents extravasation of blood products into the brain to protect neural tissue and maintain a homeostatic environment. The BBB functions as part of the neurovascular unit (NVU), which is composed of neurons, astrocytes, and microglia in addition to the specialized endothelial cells, mural cells, and the basement membrane. Through coordinated intercellular signaling, these cells function as a dynamic unit to tightly regulate brain blood flow, vascular function, neuroimmune responses, and waste clearance. In this chapter, we review the functions of individual NVU components, describe neurovascular coupling as a classic example of NVU function, and discuss archetypal NVU pathophysiology during disease.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Iadecola C (2017) The neurovascular unit coming of age: a journey through neurovascular coupling in health and disease. Neuron 96:17–42

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Mcconnell HL, Li Z, Woltjer RL et al (2019) Astrocyte dysfunction and neurovascular impairment in neurological disorders: correlation or causation? Neurochem Int 128:70–84

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Lovick TA, Brown LA, Key BJ (1999) Neurovascular relationships in hippocampal slices: physiological and anatomical studies of mechanisms underlying flow-metabolism coupling in intraparenchymal microvessels. Neuroscience 92:47–60

    Article  CAS  PubMed  Google Scholar 

  4. Blinder P, Tsai PS, Kaufhold JP et al (2013) The cortical angiome: an interconnected vascular network with noncolumnar patterns of blood flow. Nat Neurosci 16:889–897

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Xie L, Kang H, Xu Q et al (2013) Sleep drives metabolite clearance from the adult brain. Science 342:373–377

    Article  CAS  PubMed  Google Scholar 

  6. Kisler K, Nelson AR, Montagne A et al (2017) Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease. Nat Rev Neurosci 18:419–434

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Butt AM, Jones HC, Abbott NJ (1990) Electrical resistance across the blood-brain barrier in anaesthetized rats: a developmental study. J Physiol 429:47–62

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Pluimer BR, Colt M, Zhao Z (2020) G protein-coupled receptors in the mammalian blood-brain barrier. Front Cell Neurosci 14:139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Cornford EM, Hyman S (2005) Localization of brain endothelial luminal and abluminal transporters with immunogold electron microscopy. NeuroRx 2:27–43

    Article  PubMed  PubMed Central  Google Scholar 

  10. Andreone BJ, Chow BW, Tata A et al (2017) Blood-brain barrier permeability is regulated by lipid transport-dependent suppression of caveolae-mediated transcytosis. Neuron 94:581–594 e585

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Chow BW, Gu C (2017) Gradual suppression of transcytosis governs functional blood-retinal barrier formation. Neuron 93:1325–1333 e1323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Keaney J, Walsh DM, O'malley T et al (2015) Autoregulated paracellular clearance of amyloid-beta across the blood-brain barrier. Sci Adv 1:e1500472

    Article  PubMed  PubMed Central  Google Scholar 

  13. Urayama A, Grubb JH, Sly WS et al (2004) Developmentally regulated mannose 6-phosphate receptor-mediated transport of a lysosomal enzyme across the blood-brain barrier. Proc Natl Acad Sci U S A 101:12658–12663

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Pardridge WM, Triguero D, Yang J et al (1990) Comparison of in vitro and in vivo models of drug transcytosis through the blood-brain barrier. J Pharmacol Exp Ther 253:884–891

    CAS  PubMed  Google Scholar 

  15. Lombardo SM, Schneider M, Tureli AE et al (2020) Key for crossing the bbb with nanoparticles: the rational design. Beilstein J Nanotechnol 11:866–883

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Matsumoto J, Stewart T, Sheng L et al (2017) Transmission of alpha-synuclein-containing erythrocyte-derived extracellular vesicles across the blood-brain barrier via adsorptive mediated transcytosis: another mechanism for initiation and progression of Parkinson's disease? Acta Neuropathol Commun 5:71

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Daneman R, Zhou L, Agalliu D et al (2010) The mouse blood-brain barrier transcriptome: a new resource for understanding the development and function of brain endothelial cells. PLoS One 5:e13741

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. He L, Vanlandewijck M, Mae MA et al (2018) Single-cell RNA sequencing of mouse brain and lung vascular and vessel-associated cell types. Sci Data 5:180160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Jambusaria A, Hong Z, Zhang L et al (2020) Endothelial heterogeneity across distinct vascular beds during homeostasis and inflammation. elife 9:e51413

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lochhead JJ, Yang J, Ronaldson PT et al (2020) Structure, function, and regulation of the blood-brain barrier tight junction in central nervous system disorders. Front Physiol 11:914

    Article  PubMed  PubMed Central  Google Scholar 

  21. Ganong WF (2000) Circumventricular organs: definition and role in the regulation of endocrine and autonomic function. Clin Exp Pharmacol Physiol 27:422–427

    Article  CAS  PubMed  Google Scholar 

  22. Rodriguez EM, Blazquez JL, Guerra M (2010) The design of barriers in the hypothalamus allows the median eminence and the arcuate nucleus to enjoy private milieus: the former opens to the portal blood and the latter to the cerebrospinal fluid. Peptides 31:757–776

    Article  CAS  PubMed  Google Scholar 

  23. Cuddapah VA, Zhang SL, Sehgal A (2019) Regulation of the blood-brain barrier by circadian rhythms and sleep. Trends Neurosci 42:500–510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Zhang SL, Yue Z, Arnold DM et al (2018) A circadian clock in the blood-brain barrier regulates xenobiotic efflux. Cell 173:130–139 e110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gomez-Gonzalez B, Hurtado-Alvarado G, Esqueda-Leon E et al (2013) Rem sleep loss and recovery regulates blood-brain barrier function. Curr Neurovasc Res 10:197–207

    Article  CAS  PubMed  Google Scholar 

  26. Atochin DN, Huang PL (2011) Role of endothelial nitric oxide in cerebrovascular regulation. Curr Pharm Biotechnol 12:1334–1342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hogan-Cann AD, Lu P, Anderson CM (2019) Endothelial NMDA receptors mediate activity-dependent brain hemodynamic responses in mice. Proc Natl Acad Sci U S A 116:10229–10231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Stobart JL, Lu L, Anderson HD et al (2013) Astrocyte-induced cortical vasodilation is mediated by d-serine and endothelial nitric oxide synthase. Proc Natl Acad Sci U S A 110:3149–3154

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Howarth C, Mishra A, Hall CN (2021) More than just summed neuronal activity: how multiple cell types shape the bold response. Philos Trans R Soc Lond Ser B Biol Sci 376:20190630

    Article  Google Scholar 

  30. Kovacs-Oller T, Ivanova E, Bianchimano P et al (2019) Dynamic connectivity maps of pericytes and endothelial cells mediate neurovascular coupling in health and disease. bioRxiv:830398

    Google Scholar 

  31. Davidson SM, Duchen MR (2007) Endothelial mitochondria: contributing to vascular function and disease. Circ Res 100:1128–1141

    Article  CAS  PubMed  Google Scholar 

  32. Castro Dias M, Mapunda JA, Vladymyrov M et al (2019) Structure and junctional complexes of endothelial, epithelial and glial brain barriers. Int J Mol Sci 20:5372

    Article  PubMed Central  CAS  Google Scholar 

  33. Stratman AN, Malotte KM, Mahan RD et al (2009) Pericyte recruitment during vasculogenic tube assembly stimulates endothelial basement membrane matrix formation. Blood 114:5091–5101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Menezes MJ, Mcclenahan FK, Leiton CV et al (2014) The extracellular matrix protein laminin alpha2 regulates the maturation and function of the blood-brain barrier. J Neurosci 34:15260–15280

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Xu L, Nirwane A, Yao Y (2019) Basement membrane and blood-brain barrier. Stroke Vasc Neurol 4:78–82

    Article  PubMed  Google Scholar 

  36. Ceafalan LC, Fertig TE, Gheorghe TC et al (2019) Age-related ultrastructural changes of the basement membrane in the mouse blood-brain barrier. J Cell Mol Med 23:819–827

    Article  CAS  PubMed  Google Scholar 

  37. Robel S, Mori T, Zoubaa S et al (2009) Conditional deletion of beta1-integrin in astroglia causes partial reactive gliosis. Glia 57:1630–1647

    Article  PubMed  Google Scholar 

  38. Bonkowski D, Katyshev V, Balabanov RD et al (2011) The cns microvascular pericyte: Pericyte-astrocyte crosstalk in the regulation of tissue survival. Fluids Barriers CNS 8:8

    Article  PubMed  PubMed Central  Google Scholar 

  39. Smyth LCD, Rustenhoven J, Scotter EL et al (2018) Markers for human brain pericytes and smooth muscle cells. J Chem Neuroanat 92:48–60

    Article  CAS  PubMed  Google Scholar 

  40. Armulik A, Genove G, Betsholtz C (2011) Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev Cell 21:193–215

    Article  CAS  PubMed  Google Scholar 

  41. Geevarghese A, Herman IM (2014) Pericyte-endothelial crosstalk: implications and opportunities for advanced cellular therapies. Transl Res 163:296–306

    Article  PubMed  PubMed Central  Google Scholar 

  42. Daneman R, Zhou L, Kebede AA et al (2010) Pericytes are required for blood-brain barrier integrity during embryogenesis. Nature 468:562–566

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Gaengel K, Genove G, Armulik A et al (2009) Endothelial-mural cell signaling in vascular development and angiogenesis. Arterioscler Thromb Vasc Biol 29:630–638

    Article  CAS  PubMed  Google Scholar 

  44. Hall CN, Reynell C, Gesslein B et al (2014) Capillary pericytes regulate cerebral blood flow in health and disease. Nature 508:55–60

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Korn C, Augustin HG (2015) Mechanisms of vessel pruning and regression. Dev Cell 34:5–17

    Article  CAS  PubMed  Google Scholar 

  46. Armulik A, Genove G, Mae M et al (2010) Pericytes regulate the blood-brain barrier. Nature 468:557–561

    Article  CAS  PubMed  Google Scholar 

  47. Gundersen GA, Vindedal GF, Skare O et al (2014) Evidence that pericytes regulate aquaporin-4 polarization in mouse cortical astrocytes. Brain Struct Funct 219:2181–2186

    Article  CAS  PubMed  Google Scholar 

  48. Attwell D, Mishra A, Hall CN et al (2016) What is a pericyte? J Cereb Blood Flow Metab 36:451–455

    Article  CAS  PubMed  Google Scholar 

  49. Grant RI, Hartmann DA, Underly RG et al (2019) Organizational hierarchy and structural diversity of microvascular pericytes in adult mouse cortex. J Cereb Blood Flow Metab 39:411–425

    Article  PubMed  Google Scholar 

  50. Berthiaume AA, Hartmann DA, Majesky MW et al (2018) Pericyte structural remodeling in cerebrovascular health and homeostasis. Front Aging Neurosci 10:210

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Gonzales AL, Klug NR, Moshkforoush A et al (2020) Contractile pericytes determine the direction of blood flow at capillary junctions. Proc Natl Acad Sci U S A 117:27022–27033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Mishra A, Reynolds JP, Chen Y et al (2016) Astrocytes mediate neurovascular signaling to capillary pericytes but not to arterioles. Nat Neurosci 19:1619–1627

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Alarcon-Martinez L, Yilmaz-Ozcan S, Yemisci M et al (2019) Retinal ischemia induces alpha-SMA-mediated capillary pericyte contraction coincident with perivascular glycogen depletion. Acta Neuropathol Commun 7:134

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Bandopadhyay R, Orte C, Lawrenson JG et al (2001) Contractile proteins in pericytes at the blood-brain and blood-retinal barriers. J Neurocytol 30:35–44

    Article  CAS  PubMed  Google Scholar 

  55. Nehls V, Drenckhahn D (1991) Heterogeneity of microvascular pericytes for smooth muscle type alpha-actin. J Cell Biol 113:147–154

    Article  CAS  PubMed  Google Scholar 

  56. Hartmann DA, Berthiaume AA, Grant RI et al (2021) Brain capillary pericytes exert a substantial but slow influence on blood flow. Nat Neurosci 24: 633–645

    Google Scholar 

  57. Arango-Lievano M, Boussadia B, De Terdonck LDT et al (2018) Topographic reorganization of cerebrovascular mural cells under seizure conditions. Cell Rep 23:1045–1059

    Article  CAS  PubMed  Google Scholar 

  58. Grubb S, Cai C, Hald BO et al (2020) Precapillary sphincters maintain perfusion in the cerebral cortex. Nat Commun 11:395

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Montagne A, Nikolakopoulou AM, Zhao Z et al (2018) Pericyte degeneration causes white matter dysfunction in the mouse central nervous system. Nat Med 24:326–337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Cai C, Fordsmann JC, Jensen SH et al (2018) Stimulation-induced increases in cerebral blood flow and local capillary vasoconstriction depend on conducted vascular responses. Proc Natl Acad Sci U S A 115:E5796–E5804

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Rungta RL, Chaigneau E, Osmanski BF et al (2018) Vascular compartmentalization of functional hyperemia from the synapse to the pia. Neuron 99:362–375 e364

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Nelson AR, Sagare MA, Wang Y et al (2020) Channelrhodopsin excitation contracts brain pericytes and reduces blood flow in the aging mouse brain in vivo. Front Aging Neurosci 12:108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Profaci CP, Munji RN, Pulido RS et al (2020) The blood-brain barrier in health and disease: Important unanswered questions. J Exp Med 217:e20190062

    Article  PubMed  PubMed Central  Google Scholar 

  64. Proebstl D, Voisin MB, Woodfin A et al (2012) Pericytes support neutrophil subendothelial cell crawling and breaching of venular walls in vivo. J Exp Med 209:1219–1234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Sims DE, Miller FN, Donald A et al (1990) Ultrastructure of pericytes in early stages of histamine-induced inflammation. J Morphol 206:333–342

    Article  CAS  PubMed  Google Scholar 

  66. Damisah EC, Hill RA, Tong L et al (2017) A fluoro-Nissl dye identifies pericytes as distinct vascular mural cells during in vivo brain imaging. Nat Neurosci 20:1023–1032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Attwell D, Buchan AM, Charpak S et al (2010) Glial and neuronal control of brain blood flow. Nature 468:232–243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Iadecola C, Nedergaard M (2007) Glial regulation of the cerebral microvasculature. Nat Neurosci 10:1369–1376

    Article  CAS  PubMed  Google Scholar 

  69. Christ GJ, Spray DC, El-Sabban M et al (1996) Gap junctions in vascular tissues. Evaluating the role of intercellular communication in the modulation of vasomotor tone. Circ Res 79:631–646

    Article  CAS  PubMed  Google Scholar 

  70. Welsh DG, Tran CHT, Hald BO et al (2018) The conducted vasomotor response: function, biophysical basis, and pharmacological control. Annu Rev Pharmacol Toxicol 58:391–410

    Article  CAS  PubMed  Google Scholar 

  71. Seppey D, Sauser R, Koenigsberger M et al (2010) Intercellular calcium waves are associated with the propagation of vasomotion along arterial strips. Am J Physiol Heart Circ Physiol 298:H488–H496

    Article  CAS  PubMed  Google Scholar 

  72. Aldea R, Weller RO, Wilcock DM et al (2019) Cerebrovascular smooth muscle cells as the drivers of intramural periarterial drainage of the brain. Front Aging Neurosci 11:1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Mathiisen TM, Lehre KP, Danbolt NC et al (2010) The perivascular astroglial sheath provides a complete covering of the brain microvessels: an electron microscopic 3d reconstruction. Glia 58:1094–1103

    Article  PubMed  Google Scholar 

  74. Sofroniew MV, Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropathol 119:7–35

    Article  PubMed  Google Scholar 

  75. Batiuk MY, Martirosyan A, Wahis J et al (2020) Identification of region-specific astrocyte subtypes at single cell resolution. Nat Commun 11:1220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Bayraktar OA, Bartels T, Holmqvist S et al (2020) Astrocyte layers in the mammalian cerebral cortex revealed by a single-cell in situ transcriptomic map. Nat Neurosci 23:500–509

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Chai H, Diaz-Castro B, Shigetomi E et al (2017) Neural circuit-specialized astrocytes: transcriptomic, proteomic, morphological, and functional evidence. Neuron 95:531–549 e539

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. John Lin CC, Yu K, Hatcher A et al (2017) Identification of diverse astrocyte populations and their malignant analogs. Nat Neurosci 20:396–405

    Article  CAS  PubMed  Google Scholar 

  79. Tsai HH, Li H, Fuentealba LC et al (2012) Regional astrocyte allocation regulates cns synaptogenesis and repair. Science 337:358–362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Farmer WT, Abrahamsson T, Chierzi S et al (2016) Neurons diversify astrocytes in the adult brain through sonic hedgehog signaling. Science 351:849–854

    Article  CAS  PubMed  Google Scholar 

  81. Lee ML, Martinez-Lozada Z, Krizman EN et al (2017) Brain endothelial cells induce astrocytic expression of the glutamate transporter glt-1 by a notch-dependent mechanism. J Neurochem 143:489–506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Mi H, Haeberle H, Barres BA (2001) Induction of astrocyte differentiation by endothelial cells. J Neurosci 21:1538–1547

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Hu X, Qin S, Huang X et al (2019) Region-restrict astrocytes exhibit heterogeneous susceptibility to neuronal reprogramming. Stem Cell Rep 12:290–304

    Article  CAS  Google Scholar 

  84. Ziemens D, Oschmann F, Gerkau NJ et al (2019) Heterogeneity of activity-induced sodium transients between astrocytes of the mouse hippocampus and neocortex: mechanisms and consequences. J Neurosci 39:2620–2634

    Article  PubMed  PubMed Central  Google Scholar 

  85. Rusnakova V, Honsa P, Dzamba D et al (2013) Heterogeneity of astrocytes: from development to injury - single cell gene expression. PLoS One 8:e69734

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Scemes E, Spray DC (2003) The astrocyte syncytium non-neural cells in the nervous system. Elsevier, pp 165–179

    Google Scholar 

  87. Araque A, Carmignoto G, Haydon PG et al (2014) Gliotransmitters travel in time and space. Neuron 81:728–739

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Boulay AC, Saubamea B, Adam N et al (2017) Translation in astrocyte distal processes sets molecular heterogeneity at the gliovascular interface. Cell Discov 3:17005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Li L, Acioglu C, Heary RF et al (2021) Role of astroglial toll-like receptors (TLRs) in central nervous system infections, injury and neurodegenerative diseases. Brain Behav Immun 91:740–755

    Article  CAS  PubMed  Google Scholar 

  90. Yao Y, Chen ZL, Norris EH et al (2014) Astrocytic laminin regulates pericyte differentiation and maintains blood brain barrier integrity. Nat Commun 5:3413

    Article  PubMed  CAS  Google Scholar 

  91. Garcia CM, Darland DC, Massingham LJ et al (2004) Endothelial cell-astrocyte interactions and TGF beta are required for induction of blood-neural barrier properties. Brain Res Dev Brain Res 152:25–38

    Article  CAS  PubMed  Google Scholar 

  92. Kacem K, Lacombe P, Seylaz J et al (1998) Structural organization of the perivascular astrocyte endfeet and their relationship with the endothelial glucose transporter: a confocal microscopy study. Glia 23:1–10

    Article  CAS  PubMed  Google Scholar 

  93. Amiry-Moghaddam M, Williamson A, Palomba M et al (2003) Delayed k+ clearance associated with aquaporin-4 mislocalization: phenotypic defects in brains of alpha-syntrophin-null mice. Proc Natl Acad Sci U S A 100:13615–13620

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Ishii M, Horio Y, Tada Y et al (1997) Expression and clustered distribution of an inwardly rectifying potassium channel, kab-2/kir4.1, on mammalian retinal Muller cell membrane: their regulation by insulin and laminin signals. J Neurosci 17:7725–7735

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Manley GT, Fujimura M, Ma T et al (2000) Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke. Nat Med 6:159–163

    Article  CAS  PubMed  Google Scholar 

  96. Bazargani N, Attwell D (2016) Astrocyte calcium signaling: the third wave. Nat Neurosci 19:182–189

    Article  CAS  PubMed  Google Scholar 

  97. Covelo A, Araque A (2018) Neuronal activity determines distinct gliotransmitter release from a single astrocyte. elife 7:e32237

    Article  PubMed  PubMed Central  Google Scholar 

  98. Mederos S, Sanchez-Puelles C, Esparza J et al (2021) Gabaergic signaling to astrocytes in the prefrontal cortex sustains goal-directed behaviors. Nat Neurosci 24:82–92

    Article  CAS  PubMed  Google Scholar 

  99. Shigetomi E, Jackson-Weaver O, Huckstepp RT et al (2013) Trpa1 channels are regulators of astrocyte basal calcium levels and long-term potentiation via constitutive d-serine release. J Neurosci 33:10143–10153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Pacholko AG, Wotton CA, Bekar LK (2020) Astrocytes-the ultimate effectors of long-range neuromodulatory networks? Front Cell Neurosci 14:581075

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Rouach N, Koulakoff A, Abudara V et al (2008) Astroglial metabolic networks sustain hippocampal synaptic transmission. Science 322:1551–1555

    Article  CAS  PubMed  Google Scholar 

  102. Murphy-Royal C, Johnston AD, Boyce AKJ et al (2020) Stress gates an astrocytic energy reservoir to impair synaptic plasticity. Nat Commun 11:2014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Clasadonte J, Scemes E, Wang Z et al (2017) Connexin 43-mediated astroglial metabolic networks contribute to the regulation of the sleep-wake cycle. Neuron 95:1365–1380 e1365

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Mishra A (2017) Binaural blood flow control by astrocytes: listening to synapses and the vasculature. J Physiol 595:1885–1902

    Article  CAS  PubMed  Google Scholar 

  105. Rosenegger DG, Tran CH, Wamsteeker Cusulin JI et al (2015) Tonic local brain blood flow control by astrocytes independent of phasic neurovascular coupling. J Neurosci 35:13463–13474

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Kim KJ, Iddings JA, Stern JE et al (2015) Astrocyte contributions to flow/pressure-evoked parenchymal arteriole vasoconstriction. J Neurosci 35:8245–8257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Kur J, Newman EA (2014) Purinergic control of vascular tone in the retina. J Physiol 592:491–504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Biesecker KR, Srienc AI, Shimoda AM et al (2016) Glial cell calcium signaling mediates capillary regulation of blood flow in the retina. J Neurosci 36:9435–9445

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Institoris A, Rosenegger DG, Gordon GR (2015) Arteriole dilation to synaptic activation that is sub-threshold to astrocyte endfoot ca2+ transients. J Cereb Blood Flow Metab 35:1411–1415

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Gu X, Chen W, Volkow ND et al (2018) Synchronized astrocytic ca(2+) responses in neurovascular coupling during somatosensory stimulation and for the resting state. Cell Rep 23:3878–3890

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Iliff JJ, Wang M, Liao Y et al (2012) A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci Transl Med 4:147ra111

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Liu DX, He X, Wu D et al (2017) Continuous theta burst stimulation facilitates the clearance efficiency of the glymphatic pathway in a mouse model of sleep deprivation. Neurosci Lett 653:189–194

    Article  CAS  PubMed  Google Scholar 

  113. Kress BT, Iliff JJ, Xia M et al (2014) Impairment of paravascular clearance pathways in the aging brain. Ann Neurol 76:845–861

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Thion MS, Ginhoux F, Garel S (2018) Microglia and early brain development: an intimate journey. Science 362:185–189

    Article  CAS  PubMed  Google Scholar 

  115. Coelho-Santos V, Shih AY (2020) Postnatal development of cerebrovascular structure and the neurogliovascular unit. Wiley Interdiscip Rev Dev Biol 9:e363

    Article  PubMed  Google Scholar 

  116. Rymo SF, Gerhardt H, Wolfhagen Sand F et al (2011) A two-way communication between microglial cells and angiogenic sprouts regulates angiogenesis in aortic ring cultures. PLoS One 6:e15846

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Fantin A, Vieira JM, Gestri G et al (2010) Tissue macrophages act as cellular chaperones for vascular anastomosis downstream of VEGF-mediated endothelial tip cell induction. Blood 116:829–840

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Mondo E, Becker SC, Kautzman AG et al (2020) A developmental analysis of juxtavascular microglia dynamics and interactions with the vasculature. J Neurosci 40:6503–6521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Tanaka T, Ueno M, Yamashita T (2009) Engulfment of axon debris by microglia requires p38 MAPK activity. J Biol Chem 284:21626–21636

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Fenn AM, Hall JC, Gensel JC et al (2014) Il-4 signaling drives a unique arginase+/il-1beta+ microglia phenotype and recruits macrophages to the inflammatory cns: consequences of age-related deficits in il-4ralpha after traumatic spinal cord injury. J Neurosci 34:8904–8917

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Liddelow SA, Guttenplan KA, Clarke LE et al (2017) Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541:481–487

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Shinozaki Y, Shibata K, Yoshida K et al (2017) Transformation of astrocytes to a neuroprotective phenotype by microglia via p2y1 receptor downregulation. Cell Rep 19:1151–1164

    Article  CAS  PubMed  Google Scholar 

  123. Haruwaka K, Ikegami A, Tachibana Y et al (2019) Dual microglia effects on blood brain barrier permeability induced by systemic inflammation. Nat Commun 10:5816

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Jolivel V, Bicker F, Biname F et al (2015) Perivascular microglia promote blood vessel disintegration in the ischemic penumbra. Acta Neuropathol 129:279–295

    Article  PubMed  Google Scholar 

  125. Halder SK, Milner R (2019) A critical role for microglia in maintaining vascular integrity in the hypoxic spinal cord. Proc Natl Acad Sci U S A 116:26029–26037

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Boche D, Perry VH, Nicoll JA (2013) Review: activation patterns of microglia and their identification in the human brain. Neuropathol Appl Neurobiol 39:3–18

    Article  CAS  PubMed  Google Scholar 

  127. Ronaldson PT, Davis TP (2020) Regulation of blood-brain barrier integrity by microglia in health and disease: a therapeutic opportunity. J Cereb Blood Flow Metab :271678X20951995

    Google Scholar 

  128. Thurgur H, Pinteaux E (2019) Microglia in the neurovascular unit: blood-brain barrier-microglia interactions after central nervous system disorders. Neuroscience 405:55–67

    Article  CAS  PubMed  Google Scholar 

  129. Xing C, Li W, Deng W et al (2018) A potential gliovascular mechanism for microglial activation: differential phenotypic switching of microglia by endothelium versus astrocytes. J Neuroinflammation 15:143

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Osipova ED, Semyachkina-Glushkovskaya OV, Morgun AV et al (2018) Gliotransmitters and cytokines in the control of blood-brain barrier permeability. Rev Neurosci 29:567–591

    Article  CAS  PubMed  Google Scholar 

  131. Logothetis NK (2003) The underpinnings of the bold functional magnetic resonance imaging signal. J Neurosci 23:3963–3971

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Raichle ME (1998) Behind the scenes of functional brain imaging: a historical and physiological perspective. Proc Natl Acad Sci U S A 95:765–772

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Fox PT, Mintun MA, Raichle ME et al (1986) Mapping human visual cortex with positron emission tomography. Nature 323:806–809

    Article  CAS  PubMed  Google Scholar 

  134. Frackowiak RS, Friston KJ (1994) Functional neuroanatomy of the human brain: positron emission tomography--a new neuroanatomical technique. J Anat 184(Pt 2):211–225

    PubMed  PubMed Central  Google Scholar 

  135. Mace E, Montaldo G, Osmanski BF et al (2013) Functional ultrasound imaging of the brain: theory and basic principles. IEEE Trans Ultrason Ferroelectr Freq Control 60:492–506

    Article  PubMed  Google Scholar 

  136. Schulz K, Sydekum E, Krueppel R et al (2012) Simultaneous bold fMRI and fiber-optic calcium recording in rat neocortex. Nat Methods 9:597–602

    Article  CAS  PubMed  Google Scholar 

  137. Jiao H, Wang Z, Liu Y et al (2011) Specific role of tight junction proteins claudin-5, occludin, and zo-1 of the blood-brain barrier in a focal cerebral ischemic insult. J Mol Neurosci 44:130–139

    Article  CAS  PubMed  Google Scholar 

  138. Yang Y, Estrada EY, Thompson JF et al (2007) Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat. J Cereb Blood Flow Metab 27:697–709

    Article  CAS  PubMed  Google Scholar 

  139. Sweeney MD, Sagare AP, Zlokovic BV (2018) Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol 14:133–150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Li Y, Li M, Yang L et al (2019) The relationship between blood-brain barrier permeability and enlarged perivascular spaces: a cross-sectional study. Clin Interv Aging 14:871–878

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Krueger M, Bechmann I, Immig K et al (2015) Blood-brain barrier breakdown involves four distinct stages of vascular damage in various models of experimental focal cerebral ischemia. J Cereb Blood Flow Metab 35:292–303

    Article  CAS  PubMed  Google Scholar 

  142. Halliday MR, Rege SV, Ma Q et al (2016) Accelerated pericyte degeneration and blood-brain barrier breakdown in apolipoprotein e4 carriers with Alzheimer's disease. J Cereb Blood Flow Metab 36:216–227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Kisler K, Nelson AR, Rege SV et al (2017) Pericyte degeneration leads to neurovascular uncoupling and limits oxygen supply to brain. Nat Neurosci 20:406–416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Watson AN, Berthiaume AA, Faino AV et al (2020) Mild pericyte deficiency is associated with aberrant brain microvascular flow in aged PDGFRbeta(+/−) mice. J Cereb Blood Flow Metab 40:2387–2400

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Chen A, Akinyemi RO, Hase Y et al (2016) Frontal white matter hyperintensities, clasmatodendrosis and gliovascular abnormalities in ageing and post-stroke dementia. Brain 139:242–258

    Article  PubMed  Google Scholar 

  146. Early AN, Gorman AA, Van Eldik LJ et al (2020) Effects of advanced age upon astrocyte-specific responses to acute traumatic brain injury in mice. J Neuroinflammation 17:115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Yamashita T, Kamiya T, Deguchi K et al (2009) Dissociation and protection of the neurovascular unit after thrombolysis and reperfusion in ischemic rat brain. J Cereb Blood Flow Metab 29:715–725

    Article  CAS  PubMed  Google Scholar 

  148. Fukuda S, Fini CA, Mabuchi T et al (2004) Focal cerebral ischemia induces active proteases that degrade microvascular matrix. Stroke 35:998–1004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Zlokovic BV (2008) The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57:178–201

    Article  CAS  PubMed  Google Scholar 

  150. Ivens S, Kaufer D, Flores LP et al (2007) Tgf-beta receptor-mediated albumin uptake into astrocytes is involved in neocortical epileptogenesis. Brain 130:535–547

    Article  PubMed  Google Scholar 

  151. Piao CS, Holloway AL, Hong-Routson S et al (2019) Depression following traumatic brain injury in mice is associated with down-regulation of hippocampal astrocyte glutamate transporters by thrombin. J Cereb Blood Flow Metab 39:58–73

    Article  CAS  PubMed  Google Scholar 

  152. Schachtrup C, Ryu JK, Helmrick MJ et al (2010) Fibrinogen triggers astrocyte scar formation by promoting the availability of active TGF-beta after vascular damage. J Neurosci 30:5843–5854

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Sofroniew MV (2020) Astrocyte reactivity: subtypes, states, and functions in cns innate immunity. Trends Immunol 41:758–770

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Dong Y, Benveniste EN (2001) Immune function of astrocytes. Glia 36:180–190

    Article  CAS  PubMed  Google Scholar 

  155. Kim RY, Hoffman AS, Itoh N et al (2014) Astrocyte CCL2 sustains immune cell infiltration in chronic experimental autoimmune encephalomyelitis. J Neuroimmunol 274:53–61

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Moreno M, Bannerman P, Ma J et al (2014) Conditional ablation of astroglial CCL2 suppresses CNS accumulation of M1 macrophages and preserves axons in mice with MOG peptide EAE. J Neurosci 34:8175–8185

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  157. Cekanaviciute E, Dietrich HK, Axtell RC et al (2014) Astrocytic TGF-beta signaling limits inflammation and reduces neuronal damage during central nervous system toxoplasma infection. J Immunol 193:139–149

    Article  CAS  PubMed  Google Scholar 

  158. Anderson MA, Burda JE, Ren Y et al (2016) Astrocyte scar formation aids central nervous system axon regeneration. Nature 532:195–200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Faulkner JR, Herrmann JE, Woo MJ et al (2004) Reactive astrocytes protect tissue and preserve function after spinal cord injury. J Neurosci 24:2143–2155

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Herrmann JE, Imura T, Song B et al (2008) Stat3 is a critical regulator of astrogliosis and scar formation after spinal cord injury. J Neurosci 28:7231–7243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Clarke LE, Liddelow SA, Chakraborty C et al (2018) Normal aging induces a1-like astrocyte reactivity. Proc Natl Acad Sci U S A 115:E1896–E1905

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Zamanian JL, Xu L, Foo LC et al (2012) Genomic analysis of reactive astrogliosis. J Neurosci 32:6391–6410

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Brown WR, Thore CR (2011) Review: cerebral microvascular pathology in ageing and neurodegeneration. Neuropathol Appl Neurobiol 37:56–74

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Iturria-Medina Y, Sotero RC, Toussaint PJ et al (2016) Early role of vascular dysregulation on late-onset Alzheimer's disease based on multifactorial data-driven analysis. Nat Commun 7:11934

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Korte N, Nortley R, Attwell D (2020) Cerebral blood flow decrease as an early pathological mechanism in Alzheimer's disease. Acta Neuropathol 140:793–810

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Salinet AS, Robinson TG, Panerai RB (2015) Effects of cerebral ischemia on human neurovascular coupling, CO2 reactivity, and dynamic cerebral autoregulation. J Appl Physiol (1985) 118:170–177

    Article  Google Scholar 

  167. Vermeer SE, Hollander M, Van Dijk EJ et al (2003) Silent brain infarcts and white matter lesions increase stroke risk in the general population: the Rotterdam scan study. Stroke 34:1126–1129

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank Dr. Leslie Muldoon, Dr. Sasha Pejerrey, and Adrienne Winston for helpful comments on the manuscript and gratefully acknowledge Dr. Zhihua Wang for assistance with the immunohistochemistry shown in Fig. 1. H.L.M was supported by a Ruth L. Kirschstein National Research Service Award T32HL094294 (NIH). A.M.’s lab is supported by NIH grants R01NS110690 (NINDS), R01DA047237 (NIMH; PI Andrew Adey) and a Development Project grant under P30AG066518-01; Oregon Alzheimer Disease Research Center (NIA; PI Jeffrey Kaye).

Author information

Authors and Affiliations

  1. Department of Neurology, Jungers Center for Neurosciences Research, Oregon Health & Science University, Portland, OR, USA

    Heather L. McConnell & Anusha Mishra

  2. Office of Academic Development, Houston Methodist Research Institute, Houston, TX, USA

    Heather L. McConnell

  3. Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, USA

    Anusha Mishra

Authors
  1. Heather L. McConnell
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anusha Mishra
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anusha Mishra .

Editor information

Editors and Affiliations

  1. Discovery Pharmacology, COMPASS Pathways PLC, London, UK

    Nicole Stone

Rights and permissions

Reprints and permissions

Copyright information

© 2022 The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature

About this protocol

Check for updates. Verify currency and authenticity via CrossMark

Cite this protocol

McConnell, H.L., Mishra, A. (2022). Cells of the Blood–Brain Barrier: An Overview of the Neurovascular Unit in Health and Disease. In: Stone, N. (eds) The Blood-Brain Barrier. Methods in Molecular Biology, vol 2492. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-2289-6_1

Download citation

  • DOI: https://doi.org/10.1007/978-1-0716-2289-6_1

  • Published:

  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-2288-9

  • Online ISBN: 978-1-0716-2289-6

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation