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Astrocyte–endothelial interactions at the blood–brain barrier

Key Points

  • 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.

Abstract

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.

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Figure 1: Location of barrier sites in the CNS.
Figure 2: Cellular constituents of the blood–brain barrier.
Figure 3: Pathways across the blood–brain barrier.
Figure 4: Molecular composition of endothelial tight junctions.
Figure 5: Complex cell–cell signalling at the blood–brain barrier.
Figure 6: Astroglial–endothelial signalling under pathological conditions.

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Acknowledgements

The work performed in the authors' laboratories was supported by grants from the Wellcome Trust (N.J.A.) and the Swedish Research Council (L.R. and E.H.). Figures 2 and 6 were originally designed by E. Kraft, Göteborg, Sweden, who is gratefully acknowledged.

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Glossary

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.

Meninges

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.

Pericyte

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.

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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

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