Vascular function creation of glialvascular interface bloodbrain barrier and glianeuronevascular units

The brain tissue is separated from blood by three barrier systems: (1) the choroid plexus blood-CSF barrier in the ventricles of the brain, formed by tight junctions between the choroid plexus epithelial cells, which also produce the CSF; (2) the arachnoid blood-CSF barrier separating the subarachnoid CSF from the blood and formed by tight junctions between the cells of the arachnoid mater surrounding the brain; and (3) the blood-brain barrier between the intracerebral blood vessels and the brain parenchyma, formed by tight junctions between the endothelial cells of the blood vessels and the surrounding astroglial endfeet. The blood-brain barrier exists throughout the brain, with the exception of circumventricular organs, neurohypophysis, pineal gland, subfornical organ, and lamina terminalis, which are involved in neurosecretion and regulation of the endocrine and autonomic systems. In these parts of the brain, capillary walls are fenestrated, which allows the free exchange of large metabolites and hormones between the blood and the CNS; a permeability barrier formed by tight junctions between the cells lining the brain ventricles prevents leakage of these chemicals into the CSF and the rest of the brain tissue. In addition, junctional complexes between astrocyte endfeet that form the subpial glial limiting membranes and between ependymal cells lining the brain ventricles restrict the movement of large solutes between the brain tissue and the subarachnoid CSF and ventricular CSF, respectively.

The endothelial cells that line CNS blood vessels differ from those outside the nervous system, which determines the fundamental differences in the features of brain and non-brain capillaries (Figure 7.4). The endothelial cells in brain capillaries form numerous tight junctions, which effectively prevent paracellular transport of macromolecules or invasion of blood cells. In contrast, in nonneural capillaries the endothelial cells do not form continuous tight junctions; on the contrary the intercellular junctions are freely permeable to most solutes and in some cases capillaries have relatively large passages known as fenestrations, which allow paracellular diffusion of large molecular weight molecules and provide, when necessary, the pathway for infiltration of blood cells (i.e. macrophages) into the surrounding tissue.

From the brain side, the anatomical substrate of the blood-brain barrier is created by astroglial endfeet, which closely enwrap the capillary wall (Figure 7.4). The presence of an astroglial compartment around the blood vessels is of paramount importance for modifying the endothelial cells, as astrocytes release several regulatory factors (such as transforming growth factor a, TGFa, and glial-derived neurotrophic factor, GDNF), which induce the formation of tight junctions between endothelial cells and stimulate the polarization of their luminal and basal cell membranes (with respect to expression of various ion channels and proteins involved in transport across the blood-brain barrier). The endothelial cells, in turn also signal to astrocytes, in particular through leukaemia-inhibitory factor (LIF), which promotes astrocyte maturation. Contacts between astroglial endfeet and the endothelial cells also regulate expression of receptors and ion channels (especially aquaporins and K+ channels) in the glial membrane.

The tight junctions between endothelial cells create the barrier between brain parenchyma and the circulation, essentially forming a sealed wall to the movement of even the smallest solutes (e.g. ions). The main function of this barrier is indeed

Brain Capillary Peripheral Capillary

Figure 7.4 General structure of brain and peripheral capillaries. The scheme shows a cross-section of brain (CNS) and peripheral (systemic) capillaries. The endothelial cells of the brain capillary are sealed by tight junctions (TJ), which are the physical substrate of the blood-brain barrier and almost completely restrict diffusion of solutes between the blood and brain; hence, all solutes must pass through the endothelial cell (see Figure 7.5). Astroglial endfeet completely ensheath CNS capillaries and are important for induction and maintenance of blood-brain barrier properties and ion and water transport. In contrast, in peripheral blood vessels the intercellular junctions between endothelial cells are open and often fenestrated, and endothelial cells contain pinocytic vesicles, which are absent from most brain capillaries

Figure 7.4 General structure of brain and peripheral capillaries. The scheme shows a cross-section of brain (CNS) and peripheral (systemic) capillaries. The endothelial cells of the brain capillary are sealed by tight junctions (TJ), which are the physical substrate of the blood-brain barrier and almost completely restrict diffusion of solutes between the blood and brain; hence, all solutes must pass through the endothelial cell (see Figure 7.5). Astroglial endfeet completely ensheath CNS capillaries and are important for induction and maintenance of blood-brain barrier properties and ion and water transport. In contrast, in peripheral blood vessels the intercellular junctions between endothelial cells are open and often fenestrated, and endothelial cells contain pinocytic vesicles, which are absent from most brain capillaries to isolate the brain from the blood and provide a substrate for the brain's own homeostatic system. Everything that must cross the blood-brain barrier has to pass through the endothelial cells, which are selectively permeable to allow energy substrates and other essentials to enter, and metabolites to exit the brain tissue. The selective permeability is achieved by specific transporters residing in the endothelial cell membrane (Figure 7.5). These transporters are many and include (1) the energy-dependent adenine-nucleotide binding (ABC) cassette transporters, which excrete xenobiotics (this mainly determines the impermeability of the blood-brain barrier to many drugs, such as antibiotics, cytostatics, opioids etc.); (2) amino acid transporters; (3) glucose transporter of GLUT1 type; (4) ion exchangers etc.

Glucose Transporter Nervous System

Figure 7.5 Transporter systems in the endothelial cell. The restricted permeability of the BBB means that essential solutes must be transported through the endothelial cells, which are endowed with numerous transport systems responsible for the exchange of essential solutes between blood and brain parenchyma, e.g. glucose and amino acids.

Abbreviations: ABC - adenine-nucleotide binding (ABC) cassette transporters; L1 -amino acid transporters; GLUT1 - glucose transporter; Na+/H+, Na+ /K+, Cl-/HCO- - ion cotransporters

Figure 7.5 Transporter systems in the endothelial cell. The restricted permeability of the BBB means that essential solutes must be transported through the endothelial cells, which are endowed with numerous transport systems responsible for the exchange of essential solutes between blood and brain parenchyma, e.g. glucose and amino acids.

Abbreviations: ABC - adenine-nucleotide binding (ABC) cassette transporters; L1 -amino acid transporters; GLUT1 - glucose transporter; Na+/H+, Na+ /K+, Cl-/HCO- - ion cotransporters

Many biologically active substances (e.g. catecholamines) cannot enter the brain precisely because the endothelial cells do not have the relevant transporters.

Astrocytes are not very much involved in blood-brain barrier function per se (which is determined largely by the endothelial cells), but astrocytes are important in the regulation of the blood-brain interface as a whole. Astrocyte endfeet membranes are enriched with numerous receptors, transporters and channels which mediate glial-endothelial communication and regulate exchange through the glial— vascular interface. In particular, endfeet are endowed with glucose transporters, which facilitate glucose uptake and its distribution to neurones (see below). The perivascular membranes of astrocyte end feet are also enriched in potassium channels (Kir4.1 subtype) and water channels (aquaporin-4 subtype), which are important for potassium and water transport at the blood-brain interface. It appears that all astrocytes participate in the glial-vascular interface (by at least one endfoot), through which the astrocyte maintains the exchange between blood and its own territory, thus establishing metabolically independent glia-neurone-vascular units (see Figure 7.3). Astrocytes also play a central role in regulation of the local vascular tone, hence linking the metabolic demands of grey matter with local blood supply.

Peripheral Neuropathy Natural Treatment Options

Peripheral Neuropathy Natural Treatment Options

This guide will help millions of people understand this condition so that they can take control of their lives and make informed decisions. The ebook covers information on a vast number of different types of neuropathy. In addition, it will be a useful resource for their families, caregivers, and health care providers.

Get My Free Ebook


Post a comment