The blood–brain barrier (BBB), which is formed by the endothelial cells that line cerebral microvessels, has an important role in maintaining a precisely regulated microenvironment for reliable neuronal signalling. There is great interest in the association of brain microvessels, astrocytes and neurons to form functional 'neurovascular units', and recent studies have highlighted the importance of brain endothelial cells in this modular organization.
Three barrier layers limit and regulate molecular exchange at the interfaces between the blood and the neural tissue or its fluid spaces: the BBB between the blood and brain interstitial fluid, the choroid plexus epithelium between the blood and ventricular cerebrospinal fluid (CSF), and the arachnoid epithelium between the blood and subarachnoid CSF. Of these, the BBB exerts the greatest control over the immediate microenvironment of brain cells.
The BBB acts as a 'physical barrier' because complex tight junctions between adjacent endothelial cells force most molecular traffic to take a transcellular route. The presence of specific transport systems on the luminal and abluminal membranes regulates transcellular traffic, providing a selective 'transport barrier', and a combination of intracellular and extracellular enzymes allows the BBB to serve as a 'metabolic barrier'.
The BBB facilitates the entry of required nutrients into the brain, and excludes or effluxes potentially harmful compounds. It helps to keep separate the pools of neurotransmitters and neuroactive agents that act centrally and peripherally, and it regulates the ionic microenvironment of neurons.
Several features distinguish brain endothelium from the endothelium of most other tissues. In particular, the tight junctions are tighter and more complex in the brain endothelium. Among the molecules identified as making important contributions to tight junction structure are the transmembrane proteins occludin and the claudins. The brain endothelium also expresses several specific transport proteins at relatively high levels.
Brain capillaries are surrounded by or closely associated with several cell types, including neuronal processes and the perivascular endfeet of astrocytic glia, so it is not surprising to find synergistic inductive functions involving more than one cell type. For example, astrocytes secrete a range of factors that can induce aspects of the BBB phenotype in endothelial cells in vitro, and brain endothelium enhances the growth and differentiation of associated astrocytes.
Transmitters and modulators released by neurons, astrocytes and endothelium allow complex signalling between cells in the neurovascular unit, and many features of the BBB phenotype are subject to modulation under physiological or pathological conditions. For example, opening of the BBB's tight junctions may occur under normal conditions to allow the passage of growth factors and antibodies into the brain, and in inflammation can contribute to brain oedema.
Astrocytes occupy a strategic position between capillaries and neurons. Those that form perivascular endfeet at the BBB have a special role in ionic, amino acid, neurotransmitter and water homeostasis of the brain.
There is increasing evidence that the function of the BBB is altered in several neuropathologies, including brain oedema, epilepsy, Alzheimer's disease and Parkinson's disease. Damage to the endothelium could allow the expression of endothelial receptors that are normally downregulated, opening new communication loops between endothelium, pericytes, astrocytes and microglia that are important in barrier repair.
Reducing, halting or reversing BBB dysfunction could be of therapeutic value in conditions in which neuronal damage is secondary to or exacerbated by BBB damage. Moreover, maintaining endothelial health has the potential to delay or prevent the development of chronic neurodegeneration.
The blood–brain barrier, which is formed by the endothelial cells that line cerebral microvessels, has an important role in maintaining a precisely regulated microenvironment for reliable neuronal signalling. At present, there is great interest in the association of brain microvessels, astrocytes and neurons to form functional 'neurovascular units', and recent studies have highlighted the importance of brain endothelial cells in this modular organization. Here, we explore specific interactions between the brain endothelium, astrocytes and neurons that may regulate blood–brain barrier function. An understanding of how these interactions are disturbed in pathological conditions could lead to the development of new protective and restorative therapies.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Iadecola, C. Neurovascular regulation in the normal brain and in Alzheimer's disease. Nature Rev. Neurosci. 5, 347–360 (2004).
Anderson, C. M. & Nedergaard, M. Astrocyte-mediated control of cerebral microcirculation. Trends Neurosci. 26, 340–344 (2003).
Nedergaard, M., Ransom, B. & Goldman, S. A. New roles for astrocytes: redefining the functional architecture of the brain. Trends Neurosci. 26, 523–530 (2003).
Davson, H. & Segal, M. B. Physiology of the CSF and Blood–Brain Barriers (CRC, Boca Raton, USA, 1995).
Abbott, N. J. Evidence for bulk flow of brain interstitial fluid: significance for physiology and pathology. Neurochem. Int. 45, 545–552 (2004).
Schlageter, K. E., Molnar, P., Lapin, G. D. & Groothuis, D. R. Microvessel organization and structure in experimental brain tumors: microvessel populations with distinctive structural and functional properties. Microvasc. Res. 58, 312–328 (1999).
Risau, W. & Wolburg, H. Development of blood–brain barrier. Trends Neurosci. 13, 174–178 (1990).
Abbott, N. J. & Romero, I. A. Transporting therapeutics across the blood–brain barrier. Mol. Med. Today 2, 106–113 (1996).
Abbott, N. J. Astrocyte–endothelial interactions and blood–brain barrier permeability. J. Anat. 200, 629–638 (2002).
Begley, D. J. & Brightman, M. W. Structural and functional aspects of the blood–brain barrier. Prog. Drug Res. 61, 40–78 (2003).
Wolburg, H. & Lippoldt, A. Tight junctions of the blood–brain barrier: development, composition and regulation. Vasc. Pharmacol. 38, 323–337 (2002).
Hawkins, B. T. & Davis, T. P. The blood–brain barrier/neurovascular unit in health and disease. Pharmacol. Rev. 57, 173–185 (2005).
El-Bacha, R. S. & Minn, A. Drug metabolizing enzymes in cerebrovascular endothelial cells afford a metabolic protection to the brain. Cell. Mol. Biol. 45, 15–23 (1999).
Pardridge, W. M. Blood–brain barrier drug targeting: the future of brain drug development. Mol. Interv. 3, 90–105 (2003).
Ge, S., Song, L. & Pachter, J. S. Where is the blood–brain barrier...really? J. Neurosci. Res. 79, 421–427 (2005).
Abbott, N. J. Dynamics of CNS barriers: evolution, differentiation and modulation. Cell. Mol. Neurobiol. 25, 5–23 (2005).
Cserr, H. F. & Bundgaard, M. Blood–brain interfaces in vertebrates: a comparative approach. Am. J. Physiol. 246, R277–R288 (1984).
Brown, P. D., Davies, S. L., Speake, T. & Millar, I. D. Molecular mechanisms of cerebrospinal fluid production. Neuroscience 129, 957–970 (2004).
Chodobski, A. & Szmydynger-Chodobska, J. Choroid plexus: target for polypeptides and site of their synthesis. Microsc. Res. Tech. 52, 65–82 (2001).
Wolburg, H. in Blood–Brain Interfaces — from Ontogeny to Artificial Barriers (eds Dermietzel, R., Spray, D. & Nedergaard, M.) 77–107 (Wiley-VCH, Weinheim, Germany, in the press).
Butt, A. M., Jones, H. C. & Abbott, N. J. Electrical resistance across the blood–brain barrier in anaesthetized rats: a developmental study. J. Physiol. (Lond.) 429, 47–62 (1990).
Yu, A. et al. Knockdown of occludin expression leads to diverse phenotypic alterations in epithelial cells. Am. J. Physiol. Cell Physiol. 288, 1231–1241 (2005).
Simpson, I. A., Vanucci, S., DeJoseph, M. R. & Hawkins, R. A. Glucose transporter asymmetries in the bovine blood–brain barrier. J. Biol. Chem. 276, 12725–12729 (2001).
Schinkel, A. H. P-glycoprotein, a gatekeeper in the blood–brain barrier. Adv. Drug Deliv. Rev. 36, 179–194 (1999).
Hawkins, R. A., Peterson, D. R. & Vina, J. R. The complementary membranes forming the blood–brain barrier. IUBMB Life 54, 101–107 (2002).
O'Kane, R. & Hawkins, R. A. Na+-dependent transport of large neutral amino acids occurs at the abluminal membrane of the blood–brain barrier. Am. J. Physiol. Endocrinol. Metab. 285, E1167–E1173 (2003).
O'Kane, R. L., Martinez-Lopez, I., DeJoseph, M. R., Vina, J. R. & Hawkins, R. A. Na+-dependent glutamate transporters (EAAT1, EAAT2, and EAAT3) of the blood–brain barrier. J. Biol. Chem. 274, 31891–31895 (1999).
Abbott, N. J. in Blood–Brain Interfaces — From Ontology to Artificial Barriers (eds Dermietzel, R., Spray, D. & Nedergaard, M.) 189–208 (Wiley-VCH, Weinheim, Germany, in the press).
Davson, H. & Oldendorf, W. H. Transport in the central nervous system. Proc. R. Soc. Med. 60, 326–328 (1967).
Reichenbach, A. & Wolburg, H. in Neuroglia 2nd edn (eds Kettemann, H. & Ransom, B. R.) 19–35 (Oxford Univ. Press, New York, 2004).
Dehouck, M. -P., Meresse, S., Delorme, P., Fruchart, J. C. & Cecchelli, R. An easier, reproducible, and mass-production method to study the blood–brain barrier in vitro. J. Neurochem. 54, 1798–1801 (1990). One of the first papers to describe a reliable method for generating an endothelial–astrocyte co-culture model of the BBB tight enough for study of permeability and transport. The model has since been successful in functional and mechanistic studies.
Rubin, L. L. et al. A cell culture model of the blood–brain barrier. J. Cell Biol. 115, 1725–1735 (1991).
McAllister, M. S. et al. Mechanisms of glucose transport at the blood–brain barrier: an in vitro study. Brain Res. 904, 20–30 (2001). Uses high-resolution confocal microscopy and permeability studies to show how perivascular astrocytes influence glucose transport by the brain endothelium.
Hayashi, Y. et al. Induction of various blood–brain barrier properties in non-neuronal endothelial cells by close apposition to co-cultured astrocytes. Glia 19, 13–26 (1997).
Sobue, K. et al. Induction of blood–brain barrier properties in immortalized bovine brain endothelial cells by astrocytic factors. Neurosci. Res. 35, 155–164 (1999).
Haseloff, R. F., Blasig, I. E., Bauer, H. -C. & Bauer, H. In search of the astrocytic factor(s) modulating blood–brain barrier functions in brain capillary endothelial cells in vitro. Cell. Mol. Neurobiol. 25, 25–39 (2005).
Duport, S. et al. An in vitro blood–brain barrier model: cocultures between endothelial cells and organotypic brain slice cultures. Proc. Natl Acad. Sci. USA 95, 1840–1845 (1998).
Ramsauer, M., Krause, D. & Dermietzel, R. Angiogenesis of the blood–brain barrier in vitro and the function of cerebral pericytes. FASEB J. 16, 1274–1276 (2002). One of the first papers to study the complex interactions between endothelium, astrocytes and pericytes in vitro , giving insights into the development and maintenance of the neurovascular unit.
Zenker, D., Begley, D. J., Bratzke, H., Rübsamen-Waigmann, H. & von Briesen, H. Human blood-derived macrophages enhance barrier function of cultured primary bovine and human brain capillary endothelial cells. J. Physiol. (Lond.) 551, 1023–1032 (2003).
Schiera, G. et al. Synergistic effects of neurons and astrocytes on the differentation of brain capillary endothelial cells in culture. J. Cell. Mol. Med. 7, 165–170 (2003).
Berezowski, V., Landry, C., Dehouck, M. P., Cecchelli, R. & Fenart, L. Contribution of glial cells and pericytes to the mRNA profiles of P-glycoprotein and multidrug resistance-associated proteins in an in vitro model of the blood–brain barrier. Brain Res. 1018, 1–9 (2004).
Hori, S., Ohtsuki, S., Hosoya, K., Nakashima, E. & Terasaki, T. A pericyte-derived angiopoietin-1 multimeric complex induces occludin gene expression in brain capillary endothelial cells through Tie-2 activation in vitro. J. Neurochem. 89, 503–513 (2004).
Dohgu, S. et al. Brain pericytes contribute to the induction and up-regulation of blood–brain barrier functions through transforming growth factor-β production. Brain Res. 1038, 208–215 (2005).
Estrada, C., Bready, J. V., Berliner, J. A., Pardridge, W. M. & Cancilla, P. A. Astrocyte growth stimulation by a soluble factor produced by cerebral endothelial cells in vitro. J. Neuropathol. Exp. Neurol. 49, 539–549 (1990).
Mi, H., Haeberle, H. & Barres, B. A. Induction of astrocyte differentiation by endothelial cells. J. Neurosci. 21, 1538–1547 (2001). An elegant study that used 'panning' to separate cell types from the optic nerve, showing convincingly that endothelium-derived LIF induces astrocyte differentiation.
Mizuguchi, H., Utoguchi, N. & Mayumi, T. Preparation of glial cell extracellular matrix: a novel method to analyze glial–endothelial interaction. Brain Res. Brain Res. Protoc. 1, 339–343 (1997).
Schroeter, M. L. et al. Astrocytes enhance radical defence in capillary endothelial cells constituting the blood–brain barrier. FEBS Lett. 449, 241–244 (1999). This co-culture study shows clearly the 'mutual induction' that astrocytes and endothelial cells exert on each other — free radical defence enzymes are upregulated in both cell types when they are grown together.
Verkman, A. S. Aquaporin water channels and endothelial cell function. J. Anat. 200, 617–627 (2002).
Garcia-Segura, L. M. & McCarthy, M. M. Minireview: role of glia in neuroendocrine function. Endocrinology 145, 1082–1086 (2004).
Igarashi, Y. et al. Glial cell line-derived neurotrophic factor induces barrier function of endothelial cells forming the blood–brain barrier. Biochem. Biophys. Res. Commun. 261, 108–112 (1999).
Lee, S. -W. et al. SSeCKS regulates angiogenesis and tight junction formation in blood–brain barrier. Nature Med. 9, 900–906 (2003). One of the most elegant and comprehensive studies of astrocyte–endothelial induction in vitro , revealing the novel role of Src-suppressor C-kinase substrate (SSeCKs) and angiopoetin 1.
Huber, J. D., Egleton, R. D. & Davis, T. P. Molecular physiology and pathophysiology of tight junctions in the blood–brain barrier. Trends Neurosci. 24, 719–725 (2001).
Drewes, L. R. in Introduction to the Blood–Brain Barrier — Methodology, Biology and Pathology (ed. Pardridge, W. M.) 165–174 (Cambridge Univ. Press, Cambridge, UK, 1998).
Boado, R. J. & Pardridge, W. M. Glucose deprivation and hypoxia increase the expression of the GLUT-1 glucose transporter via a specific mRNA cis-acting regulatory element. J. Neurochem. 80, 552–554 (2002).
Pan, W., Akerstrom, V., Zhang, J., Pejovic, V. & Kastin, A. J. Modulation of feeding-related peptide/protein signals by the blood–brain barrier. J. Neurochem. 90, 455–461 (2004).
Abbott, N. J. Inflammatory mediators and modulation of blood–brain barrier permeability. Cell. Mol. Neurobiol. 20, 131–147 (2000).
Webb, A. A. & Muir, G. D. The blood–brain barrier and its role in inflammation. J. Vet. Intern. Med. 14, 399–411 (2000).
Tonra, J. R. Cerebellar susceptibility to experimental autoimmune encephalomyelitis in SJL/J mice: potential interaction of immunology with vascular anatomy. Cerebellum 1, 57–68 (2002).
Bauer, B., Hartz, A. M., Fricker, G. & Miller, D. S. Modulation of p-glycoprotein transport function at the blood–brain barrier. Exp. Biol. Med. 230, 118–127 (2005).
Nwaozuzu, O. M., Sellers, L. A. & Barrand, M. A. Signalling pathways influencing basal and H2O2-induced P-glycoprotein expression in endothelial cells derived from the blood–brain barrier. J. Neurochem. 87, 1043–1051 (2003).
Zhu, H. J. & Liu, G. Q. Glutamate up-regulates P-glycoprotein expression in rat brain microvessel endothelial cells by an NMDA receptor-mediated mechanism. Life Sci. 75, 1313–1322 (2004).
Bauer, B., Hartz, A. M. S., Fricker, G. & Miller, D. S. Pregnane X receptor up-regulation of P-glycoprotein expression and transport function at the blood–brain barrier. Mol. Pharmacol. 66, 413–419 (2004). Evidence that the nuclear PXR can upregulate Pgp function at the BBB, providing a mechanism for a number of long-term modulations of significance in physiology and pathology.
Hartz, A. M. S., Bauer, B., Fricker, G. & Miller, D. S. Rapid regulation of P-glycoprotein at the blood–brain barrier by endothelin-1. Mol. Pharmacol. 66, 387–394 (2004). Complementary to reference 62, this paper shows short-term modulation of Pgp by a signalling molecule released within the neurovascular unit.
Hansson, E. & Rönnbäck, L. Astrocytic receptors and second messenger systems. Adv. Mol. Cell Biol. 31, 475–501 (2004).
Hansson, E. & Rönnbäck, L. Astrocytes in glutamate neurotransmission. FASEB J. 9, 343–350 (1995).
Hansson, E. & Rönnbäck, L. Glial neuronal signalling in the central nervous system. FASEB J. 17, 341–348 (2003).
Andersson, A., Rönnbäck, L. & Hansson, E. Lactate induces tumour necrosis factor-α and interleukin-6 release in microglial and astroglial enriched primary cultures. J. Neurochem. 93, 1327–1333 (2005).
Kis, B. et al. Adrenomedullin regulates blood–brain barrier functions in vitro. Neuroreport 12, 4139–4142 (2001).
Brown, R. C., Mark, K. S., Egleton, R. D. & Davis, T. P. Protection against hypoxia-induced increase in blood–brain barrier permeability: role of tight junction proteins and NFκB. J. Cell Sci. 116, 693–700 (2003).
Mann, G. E., Yudilevich, D. L. & Sobrevia, L. Regulation of amino acid and glucose transport in endothelial and smooth muscle cells. Physiol. Rev. 83, 183–252 (2003).
Braet, K., Cabooter, L., Paemeleire, K. & Leybaert, L. Calcium signal communication in the central nervous system. Biol. Cell 96, 79–91 (2004).
Leybaert, L., Cabooter, L. & Braet, K. Calcium signal communication between glial and vascular brain cells. Acta Neurol. Belg. 104, 51–56 (2004).
Leybaert, L. Neurobarrier coupling in the brain: a partner of neurovascular and neurometabolic coupling? J. Cereb. Blood Flow Metab. 25, 2–16 (2005).
Régina, A. et al. Factor(s) released by glucose-deprived astrocytes enhance glucose transporter expression and activity in rat brain endothelial cells. Biochim. Biophys. Acta 1540, 233–242 (2001). One of the first papers to show that the metabolic status of astrocytes affects the way they influence the brain endothelium, which is of relevance in ischaemia and starvation.
Abbott, N. J. in Introduction to the Blood–Brain Barrier: Methodology and Biology (ed. Pardridge, W. M.) 345–353 (Cambridge Univ. Press, Cambridge, UK, 1998).
Muyderman, H. et al. α1-Adrenergic modulation of metabotropic glutamate receptor-induced calcium oscillations and glutamate release in astrocytes. J. Biol. Chem. 276, 46504–46514 (2001).
Pasti, L., Volterra, A., Pozzan, T. & Carmignoto, G. Intracellular calcium oscillations in astrocytes: a highly plastic, bidirectional form of communication between neurons and astrocytes in situ. J. Neurosci. 17, 7817–7830 (1997).
Cornell-Bell, A. H., Finkbeiner, S. M., Cooper, M. S. & Smith, S. J. Glutamate induces calcium waves in cultured astrocytes: long-range glial signalling. Science 247, 470–473 (1990).
Blomstrand, F. et al. 5-Hydroxytryptamine and glutamate modulate velocity and extent of intercellular calcium signalling in hippocampal astroglial cells in primary cultures. Neuroscience 88, 1241–1253 (1999).
Sneyd, J. et al. A model for the propagation of intercellular calcium waves. Am. J. Physiol. 266, C293–C302 (1994).
Cotrina, M. L. et al. Connexins regulate calcium signaling by controlling ATP release. Proc. Natl Acad. Sci. USA 95, 15735–15740 (1998).
Paemeleire, K. & Leybaert, L. ATP-dependent astrocyte–endothelial calcium signalling following mechanical damage to a single astrocyte in astrocyte–endothelial co-cultures. J. Neurotrauma 17, 345–358 (2000). One of the first papers to investigate the mechanisms that underlie rapid astrocyte–endothelial signalling, using cultured cells. It is now becoming possible to do this kind of experiment in brain slices.
Bezzi, P. et al. CXCR4-activated astrocyte glutamate release via TNFα: amplification by microglia triggers neurotoxicity. Nature Neurosci. 4, 702–710 (2001).
Rapoport, S. I. Blood–Brain Barrier in Physiology and Medicine (Raven, New York, USA, 1976).
Simard, M. & Nedergaard, M. The neurobiology of glia in the context of water and ion homeostasis. Neuroscience 129, 877–896 (2004).
Kofuji, P. & Newman, E. A. Potassium buffering in the central nervous system. Neuroscience 129, 1045–1056 (2004).
Price, D. L., Ludwig, J. W., Mi, H., Schwarz, T. L. & Ellisman, M. H. Distribution of rSlo Ca2+-activated K+ channels in rat astrocyte perivascular endfeet. Brain Res. 956, 183–193 (2002).
Simard, M., Arcuino, G., Takano, T., Liu, Q. S. & Nedergaard, M. Signaling at the gliovascular interface. J. Neurosci. 23, 9254–9262 (2003).
Amiry-Moghaddam, M. & Ottersen, O. P. The molecular basis of water transport in the brain. Nature Rev. Neurosci. 4, 991–1001 (2003).
Dolman, D., Drndarski, S., Abbott, N. J. & Rattray, M. Induction of aquaporin 1 but not aquaporin 4 messenger RNA in rat primary brain microvessel endothelial cells in culture. J. Neurochem. 93, 825–833 (2005).
Hansson, E. Metabotropic glutamate receptor activation induces astroglial swelling. J. Biol. Chem. 269, 21955–21961 (1994).
Hansson, E., Johansson, B. B., Westergren, I. & Rönnbäck, L. Glutamate-induced swelling of single astroglial cells in primary culture. Neuroscience 63, 1057–1066 (1994).
Liebner, S. et al. Claudin-1 and claudin-5 expression and tight junction morphology are altered in blood vessels of human glioblastoma multiforme. Acta Neuropathol. 100, 323–331 (2000).
Wolburg, H. et al. Localization of claudin-3 in tight junctions of the blood–brain barrier is selectively lost during experimental autoimmune encephalomyelitis and human glioblastoma multiforme. Acta Neuropathol. 105, 586–592 (2003).
Berzin, T. M. et al. Agrin and microvascular damage in Alzheimer's disease. Neurobiol. Aging 21, 349–355 (2000).
Warth, A., Kröger, S. & Wolburg, H. Redistribution of aquaporin-4 in human glioblastoma correlates with loss of agrin immunoreactivity from brain capillary basal laminae. Acta Neuropathol. 107, 311–318 (2004). Shows clearly the importance of the extracellular matrix in providing the scaffold for the ordering of proteins important in the function of astrocytic perivascular endfeet, and its disruption in pathology.
Minagar, A. & Alexander, J. S. Blood–brain barrier disruption in multiple sclerosis. Mult. Scler. 9, 540–549 (2003).
Abbott, N. J. et al. in Mechanisms of Drug Resistance in Epilepsy: Lessons from Oncology (ed. Ling, V.) Novartis Foundation Symposium No. 243, 38–47 (John Wiley, Chichester, UK, 2002).
Marroni, M. et al. Vascular and parenchymal mechanisms in multiple drug resistance: a lesson from human epilepsy. Curr. Drug Targets 4, 297–304 (2003).
Zlokovic, B. V. Neurovascular mechanisms of Alzheimer's neurodegeneration. Trends Neurosci. 28, 202–208 (2005).
Kortekaas, R. et al. Blood–brain barrier dysfunction in parkinsonian midbrain in vivo. Ann. Neurol. 57, 176–179 (2005). An important but controversial paper showing how modern imaging techniques can be used to investigate BBB transport function in humans, and the insight this may give into disease states.
Schwaninger, M. et al. Bradykinin induces interleukin-6 expression in astrocytes through activation of nuclear factor-κB. J. Neurochem. 73, 1461–1466 (1999).
Deli, M. A. et al. Exposure of tumor necrosis factor-α to luminal membrane of bovine capillary endothelial cells cocultured with astrocytes induces a delayed increase of permeability and cytoplasmic stress formation of actine. J. Neurosci. Res. 41, 717–726 (1995).
Didier, N. et al. Secretion of interleukin-1β by astrocytes mediates endothelin-1 and tumour necrosis factor-α effects on human brain microvascular endothelial cell permeability. J. Neurochem. 86, 246–254 (2003). Illustrates the potential complexities of signalling between cells at the BBB — even apparently direct actions may involve indirect loops and potentiating (and inhibitory) modulation.
Perry, V. H., Newman, T. A. & Cunningham, C. The impact of systemic infection on the progression of neurodegenerative disease. Nature Rev. Neurosci. 4, 103–112 (2003).
Banks, W. A. Blood–brain barrier transport of cytokines: a mechanism for neuropathology. Curr. Pharm. Des. 11, 973–984 (2005).
Watkins, L. R. & Maier, S. F. Glia: a novel drug discovery target for clinical pain. Nature Rev. Drug Discov. 2, 973–985 (2003).
Huber, J. D. et al. Inflammatory pain alters blood–brain barrier permeability and tight junctional protein expression. Am. J. Physiol. Heart Circ. Physiol. 280, H1241–H1248 (2001). Recent work has shown, rather surprisingly, that even peripheral stimuli such as inflammatory pain can open the BBB.
Abbott, N. J. Prediction of blood–brain barrier permeation in drug discovery, from in vivo, in vitro and in silico models. Drug Discov. Today: Technologies 1, 407–416 (2004).
Dietrich, J. B. Endothelial cells of the blood–brain barrier: a target for glucocorticoids and estrogens? Front. Biosci. 9, 684–693 (2004).
Krizanac-Bengez, L., Mayberg, M. R. & Janigro, D. The cerebral vasculature as a therapeutic target for neurological disorders and the role of shear stress in vascular homeostasis and pathophysiology. Neurol. Res. 26, 846–853 (2004).
Demeule, M. et al. Brain endothelial cells as pharmacological targets in brain tumors. Mol. Neurobiol. 30, 157–183 (2004).
Kaal, E. C. & Vecht, C. J. The management of brain edema in brain tumors. Curr. Opin. Oncol. 16, 593–600 (2004).
Cucullo, L., Hallene, K., Dini, G., Dal Toso, R. & Janigro, D. Glycerophosphoinositol and dexamethasone improve transendothelial electrical resistance in an in vitro study of the blood–brain barrier. Brain Res. 997, 147–151 (2004).
Brown, R. C., Mark, K. S., Egleton, R. D. & Davis, T. P. Protection against hypoxia-induced blood–brain barrier disruption: changes in intracellular calcium. Am. J. Cell Physiol. 286, C1045–C1052 (2004).
Turkel, N. A. & Ziylan, Z. Y. Protection of blood–brain barrier breakdown by nifedipine in adrenaline-induced hypertension. Int. J. Neurosci. 114, 517–528 (2004).
Preston, E. & Webster, J. A two-hour window for hypothermic modulation of early events that impact delayed opening of the rat blood–brain barrier after ischemia. Acta Neuropathol. (Berl.) 108, 406–412 (2004).
Wagner, K. R. & Zuccarello, M. Local brain hypothermia for neuroprotection in stroke treatment and aneurysm repair. Neurol. Res. 27, 238–245 (2005).
Park, S. et al. Neurovascular protection reduces early brain injury after subarachnoid hemorrhage. Stroke 35, 2412–2417 (2004).
Franzén, B. et al. Gene and protein expression profiling of human cerebral endothelial cells activated with tumor necrosis factor-α. Mol. Brain Res. 115, 130–146 (2003). With the human genome now fully sequenced, efforts are being made to identify genes and proteins of the brain endothelium that are activated in inflammation and disease, and that could therefore be useful targets for therapy and drug delivery to the brain. This is one of the first reports.
Kaya, D. et al. VEGF protects brain against focal ischemia without increasing blood–brain barrier permeability when administered intracerebro-ventricularly. J. Cereb. Blood Flow Metab. 25, 1111–1118 (2005).
Takahashi, M. & Macdonald, R. L. Vascular aspects of neuroprotection. Neurol. Res. 26, 862–869 (2004).
Rapoport, S. I. Advances in osmotic opening of the blood–brain barrier to enhance CNS chemotherapy. Expert Opin. Invest. Drugs 10, 1809–1818 (2001).
Kraemer, D. F., Fortin, D. & Neuwelt, E. A. Chemotherapeutic dose intensification for treatment of malignant brain tumors: recent developments and future directions. Curr. Neurol. Neurosci. Rep. 2, 216–224 (2002).
Farkas, A. et al. Hyperosmotic mannitol induces Src kinase-dependent phosphorylation of β-catenin in cerebral endothelial cells. J. Neurosci. Res. 80, 855–861 (2005).
Prados, M. D. et al. A randomized, double-blind, placebo-controlled, phase 2 study of RMP-7 in combination with carboplatin administered intravenously for the treatment of recurrent malignant glioma. Neuro-oncology 5, 96–103 (2003).
Ashraf, M. Z., Hussain, M. E. & Fahim, M. Antiatherosclerotic effects of dietary supplementations of garlic and turmeric: restoration of endothelial function in rats. Life. Sci. 77, 837–857 (2005).
Rohdewald, P. A review of the French maritime pine bark extract (Pycnogenol), a herbal medication with a diverse clinical pharmacology. Int. J. Clin. Pharmacol. Ther. 40, 158–168 (2002).
Bijl, M. Endothelial activation, endothelial dysfunction, and premature atherosclerosis in systemic autoimmune diseases. Neth. J. Med. 61, 273–277 (2003).
Calabresi, L., Gomaraschi, M. & Franceschini, G. Endothelial protection by high-density lipoproteins. From bench to bedside. Arterioscler. Thromb. Vasc. Biol. 23, 1724–1731 (2003).
d'Alessio, P. Aging and the endothelium. Exp. Gerontol. 39, 165–171 (2004).
Middlebrook, A. R. et al. Does aerobic fitness influence microvascular function in healthy adults at risk of developing type 2 diabetes? Diabet. Med. 22, 483–489 (2005).
Abeywardena, M. Y. & Head, R. J. Longchain n-3 polyunsaturated fatty acids and blood vessel function. Cardiovasc. Res. 52, 361–371 (2001).
De Caterina, R., Madonna, R. & Massaro, M. Effects of omega-3 fatty acids on cytokines and adhesion molecules. Curr. Atheroscler. Rep. 6, 485–491 (2004).
Harris, H. W., Rockey, D. C., Young, D. M. & Welch, W. J. Diet-induced protection against lipopolysaccharide includes increased hepatic NO production. J. Surg. Res. 82, 339–345 (1999).
Kamata, K. et al. Effects of chronic administration of fruit extract (Citrus unshiu Marc) on endothelial dysfunction in streptozotocin-induced diabetic rats. Biol. Pharm. Bull. 28, 267–270 (2005).
Hwang, J., Hodis, H. N. & Sevanian, A. Soy and alfafa phytoestrogen extracts become potent low-density lipoprotein antioxidants in the presence of acerola cherry extract. J. Agric. Food Chem. 49, 308–314 (2001).
Vera, R. et al. Soy isoflavones improve endothelial function in spontaneously hypertensive rats in an estrogen-independent manner: role of nitric-oxide synthase, superoxide, and cyclooxygenase metabolites. J. Pharmacol. Exp. Ther. 314, 1300–1309 (2005).
d'Uscio, L. V., Milstein, S., Richardson, D., Smith, L. & Katusic, Z. S. Long-term vitamin C treatment increases vascular tetrahydrobiopterin levels and nitric oxide synthase activity. Circ. Res. 92, 88–95 (2003).
Marsh, S. A., Laursen, P. B., Pat, B. K., Gobe, G. C. & Coombes, J. J. Bcl-2 in endothelial cells is increased by vitamin E and α-lipoic acid supplementation but not exercise training. J. Mol. Cell. Cardiol. 38, 445–451 (2005).
Praticò, D. Antioxidants and endothelium protection. Atherosclerosis 181, 215–224 (2005).
Rasmussen, S. E., Frederiksen, H., Struntze Krogholm, K. & Poulsen, L. Dietary proanthocyanidins: occurrence, dietary intake, bioavailability, and protection aganist cardiovascular disease. Mol. Nutr. Food Res. 49, 159–174 (2005).
Fung, T. T. et al. Diet-quality scores and plasma concentrations of markers of inflammation and endothelial dysfunction. Am. J. Clin. Nutr. 82, 163–173 (2005). This study on the effect of diet on systemic endothelial function is a useful indicator of possible ways to maintain a healthy BBB.
Youdim, K. A., Spencer, J. P., Schroeter, H. & Rice-Evans, C. Dietary flavonoids as potential neuroprotectants. Biol. Chem. 383, 503–519 (2002).
Yoshida, H. et al. Inhibitory effect of tea flavonoids on the ability of cells to oxidize low density lipoprotein. Biochem. Pharmacol. 58, 1695–1703 (1999).
Stoclet, J. C. et al. Vascular protection by dietary polyphenols. Eur. J. Pharmacol. 500, 299–313 (2004).
Kawakami, M., Sekiguchi, M., Sato, K., Kozaki, S. & Takahashi, M. Erythropoietin receptor-mediated inhibition of exocytotic glutamate release confers neuroprotection during chemical ischemia. J. Biol. Chem. 276, 39469–39475 (2001).
Martínez-Estrada, O. M. et al. Erythropoietin protects the in vitro blood–brain barrier against VEGF-induced permeability. Eur. J. Neurosci. 18, 2538–2544 (2003).
Zonta, M. et al. Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation. Nature Neurosci. 6, 43–50 (2003).
Tran, N. D., Correale, J., Schrieber, S. S. & Fisher, M. Transforming growth factor-β mediates astrocyte-specific regulation of brain endothelial anticoagulant factors. Stroke 30, 1671–1677 (1999).
Lo, E. H., Dalkara, T. & Moskowitz, M. A. Mechanisms, challenges and opportunities in stroke. Nature Rev. Neurosci. 4, 399–415 (2003).
Tomas-Camardiel, M. et al. Blood–brain barrier disruption highly induces aquaporin-4 mRNA and protein in perivascular and parenchymal astrocytes: protective effect by estradiol treatment in ovariectomized animals. J. Neurosci. Res. 80, 235–246 (2005).
Vakili, A., Kataoka, H. & Plesnila, N. Role of arginine vasopressin V1 and V2 receptors for brain damage after transient focal cerebral ischemia. J. Cereb. Blood Flow Metab. 25, 1012–1019 (2005).
Gaillard, P. J., de Boer, A. B. & Breimer, D. D. Pharmacological investigations on lipopolysaccharide-induced permeability changes in the blood–brain barrier in vitro. Microvasc. Res. 65, 24–31 (2003).
Veldhuis, W. B. et al. Interferon-β prevents cytokine-induced neutrophil infiltration and attenuates blood–brain barrier disruption. J. Cereb. Blood Flow Metab. 23, 1060–1069 (2003).
Oki, T. et al. Increased ability of peripheral blood lymphocytes to degrade laminin in multiple sclerosis. J. Neurol. Sci. 222, 7–11 (2004).
Dallasta, L. M. et al. Blood–brain barrier tight junction disruption in human immunodeficiency virus-1 encephalitis. Am. J. Pathol. 155, 1915–1927 (1999).
Berger, J. R. & Avison, M. The blood brain barrier in HIV infection. Front. Biosci. 9, 2680–2685 (2004).
Kalaria, R. N. The blood–brain barrier and cerebrovascular pathology in Alzheimer's disease. Ann. NY Acad. Sci. 893, 113–125 (1999).
Lee, G. & Bendayan, R. Functional expression and localization of P-glycoprotein in the central nervous system: relevance to the pathogenesis and treatment of neurological disorders. Pharm. Res. 21, 1313–1320 (2004).
Papadopoulos, M. C., Saadoun, S., Davies, D. C. & Bell, B. A. Emerging molecular mechanisms of brain tumour oedema. Br. J. Neurosurg. 15, 101–108 (2001).
Davies, D. C. Blood–brain barrier breakdown in septic encephalopathy and brain tumours. J. Anat. 200, 639–646 (2002).
Segal, M. B. & Zlokovic, B. V. The Blood–Brain Barrier, Amino Acids and Peptides (Kluwer Academic, Dordrecht, Boston (USA) & London (UK), 1990).
The authors declare no competing financial interests.
- Neurovascular unit
A functional unit composed of groups of neurons and their associated astrocytes, interacting with smooth muscle cells and endothelial cells on the microvessels (arterioles) responsible for their blood supply, and capable of regulating the local blood flow.
- Gliovascular unit
A proposed functional unit composed of single astrocytic glial cells and the neurons they surround, interacting with local segments of blood vessels, and capable of regulating blood flow at the arteriolar level and BBB functions at the capillary level.
- Choroid plexus
A site of production of CSF in the adult brain. It is formed by the invagination of ependymal cells into the ventricles, which become richly vascularized.
- Interstitial fluid
(ISF). The extracellular fluid filling the 'interstices' of the tissue, and bathing the cells.
- Tight junction
A belt-like region of adhesion between adjacent cells. Tight junctions regulate paracellular flux, and contribute to the maintenance of cell polarity by stopping molecules from diffusing within the plane of the membrane.
- Abluminal membrane
The endothelial cell membrane that faces away from the vessel lumen, towards the brain.
The complex arrangement of three protective membranes surrounding the brain, with a thick outer connective tissue layer (dura) overlying the barrier layer (arachnoid), and finally the thin layer covering the glia limitans (pia). The sub-arachnoid layer has a sponge-like structure filled with CSF.
- Circumventricular organs
(CVOs). Brain regions that have a rich vascular plexus with a specialized arrangement of blood vessels. The junctions between the capillary endothelial cells are not tight in the blood vessels of these regions, which allows the diffusion of large molecules. These organs include the organum vasculosum of the lamina terminalis, the subfornical organ, the median eminence and the area postrema.
- Receptor-mediated transcytosis
The mechanism for vesicle-mediated transfer of substances across the cell, the first step of which requires specific binding of the ligand to a membrane receptor, followed by internalization (endocytosis).
- Adsorptive-mediated transcytosis
The mechanism for vesicle-mediated transfer of substances across the cell, the first step of which involves nonspecific binding of the ligand to membrane surface charges, followed by internalization (endocytosis).
- Adherens junction
A cell–cell junction also known as zonula adherens, which is characterized by the intracellular insertion of microfilaments. If intermediate filaments are inserted in lieu of microfilaments, the resulting junction is referred to as a desmosome.
- Perivascular endfeet
The specialized foot-processes of perivascular astrocytes that are closely apposed to the outer surface of brain microvessels, and have specialized functions in inducing and regulating the BBB.
A cell of mesodermal origin, and contractile-phagocytic phenotype, associated with the outer surface of capillaries.
- Orthogonal arrays of particles
(OAPs). The organized arrays (square lattice) of intramembranous particles detected by the freeze–fracture technique in certain astrocyte processes. First identified on the polarized endfeet on blood vessels and in the outer glial layer (glia limitans) below the pia, they have subsequently been shown to contain specific protein complexes held together by structural proteins.
- Basal lamina
The extracellular matrix layer produced by the basal cell membrane, used as an anchoring and signalling site for cell–cell interactions.
About this article
Cite this article
Abbott, N., Rönnbäck, L. & Hansson, E. Astrocyte–endothelial interactions at the blood–brain barrier. Nat Rev Neurosci 7, 41–53 (2006). https://doi.org/10.1038/nrn1824
Fluids and Barriers of the CNS (2021)
Fluid proteomics of CSF and serum reveal important neuroinflammatory proteins in blood–brain barrier disruption and outcome prediction following severe traumatic brain injury: a prospective, observational study
Critical Care (2021)
Acta Neuropathologica Communications (2021)
Fluids and Barriers of the CNS (2021)
Astrocyte-specific hypoxia-inducible factor 1 (HIF-1) does not disrupt the endothelial barrier during hypoxia in vitro
Fluids and Barriers of the CNS (2021)