Structural and Cytochemical Peculiarities of Basement Membranes in the Zone of Formation of the Blood–Brain Barrier in Human Prenatal Ontogenesis

Abstract Idiopathic intracranial hypertension (IIH) is traditionally considered benign and characterized by symptoms related to increased intracranial pressure, including headache and impaired vision. We have previously demonstrated that brains of IIH patients exhibit patchy astrogliosis, increased perivascular expression of the water channel aquaporin-4 (AQP4) as well as degenerating pericyte processes and capillary basement membranes. Given the established association between pericyte degeneration and blood-brain barrier (BBB) dysfunction, we investigated blood protein leakage by light microscopic immunohistochemistry. We also assessed perivascular AQP4 expression by immunogold transmission electron microscopy. The study included 14 IIH patients and 14 reference (REF) subjects undergoing neurosurgery for epilepsy, aneurysm, or tumor. Evidence of BBB dysfunction, measured as area extravasated fibrinogen/fibrin, was significantly more pronounced in IIH than REF individuals. The extent of extravasated fibrinogen was positively correlated with increasing degree of astrogliosis and vascular AQP4 immunoreactivity, determined by light microscopy. Immunogold transmission electron microscopy revealed no overall changes in AQP4 expression at astrocytic vascular endfeet in IIH (n = 8) compared to REF (n = 11) individuals. Our results provide evidence of BBB leakage in IIH, signifying that IIH is a more serious neurodegenerative disease than previously considered.

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Na+-dependent transport of large neutral amino acids occurs at the abluminal membrane of the blood-brain barrier

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00193.2003 ◽

2003 ◽

Vol 285 (6) ◽

pp. E1167-E1173 ◽

Cited By ~ 68

Author(s):

Robyn L. O'Kane ◽

Richard A. Hawkins

Keyword(s):

Amino Acids ◽

Amino Acid ◽

Blood Brain Barrier ◽

Basement Membranes ◽

Brain Barrier ◽

Large Neutral Amino Acid ◽

Large Neutral Amino Acids ◽

Neutral Amino Acids ◽

Blood Brain ◽

Dependent Transport

Several Na+-dependent carriers of amino acids exist on the abluminal membrane of the blood-brain barrier (BBB). These Na+-dependent carriers are in a position to transfer amino acids from the extracellular fluid of brain to the endothelial cells and thence to the circulation. To date, carriers have been found that may remove nonessential, nitrogen-rich, or acidic (excitatory) amino acids, all of which may be detrimental to brain function. We describe here Na+-dependent transport of large neutral amino acids across the abluminal membrane of the BBB that cannot be ascribed to currently known systems. Fresh brains, from cows killed for food, were used. Microvessels were isolated, and contaminating fragments of basement membranes, astrocyte fragments, and pericytes were removed. Abluminal-enriched membrane fractions from these microvessels were prepared. Transport was Na+dependent, voltage sensitive, and inhibited by 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid, a particular inhibitor of the facilitative large neutral amino acid transporter 1 (LAT1) system. The carrier has a high affinity for leucine ( Km21 ± 7 μM) and is inhibited by other neutral amino acids, including glutamine, histidine, methionine, phenylalanine, serine, threonine, tryptophan, and tyrosine. Other established neutral amino acids may enter the brain by way of LAT1-type facilitative transport. The presence of a Na+-dependent carrier on the abluminal membrane capable of removing large neutral amino acids, most of which are essential, from brain indicates a more complex situation that has implications for the control of essential amino acid content of brain.

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Endothelial Cell Laminin Isoforms, Laminins 8 and 10, Play Decisive Roles in T Cell Recruitment across the Blood–Brain Barrier in Experimental Autoimmune Encephalomyelitis

The Journal of Cell Biology ◽

10.1083/jcb.153.5.933 ◽

2001 ◽

Vol 153 (5) ◽

pp. 933-946 ◽

Cited By ~ 324

Author(s):

Michael Sixt ◽

Britta Engelhardt ◽

Friederike Pausch ◽

Rupert Hallmann ◽

Olaf Wendler ◽

...

Keyword(s):

T Cells ◽

Endothelial Cell ◽

T Cell ◽

Experimental Autoimmune Encephalomyelitis ◽

Blood Brain Barrier ◽

Basement Membranes ◽

Brain Barrier ◽

Autoimmune Encephalomyelitis ◽

Blood Brain ◽

Experimental Autoimmune

An active involvement of blood–brain barrier endothelial cell basement membranes in development of inflammatory lesions in the central nervous system (CNS) has not been considered to date. Here we investigated the molecular composition and possible function of the extracellular matrix encountered by extravasating T lymphocytes during experimental autoimmune encephalomyelitis (EAE). Endothelial basement membranes contained laminin 8 (α4β1γ1) and/or 10 (α5β1γ1) and their expression was influenced by proinflammatory cytokines or angiostatic agents. T cells emigrating into the CNS during EAE encountered two biochemically distinct basement membranes, the endothelial (containing laminins 8 and 10) and the parenchymal (containing laminins 1 and 2) basement membranes. However, inflammatory cuffs occurred exclusively around endothelial basement membranes containing laminin 8, whereas in the presence of laminin 10 no infiltration was detectable. In vitro assays using encephalitogenic T cell lines revealed adhesion to laminins 8 and 10, whereas binding to laminins 1 and 2 could not be induced. Downregulation of integrin α6 on cerebral endothelium at sites of T cell infiltration, plus a high turnover of laminin 8 at these sites, suggested two possible roles for laminin 8 in the endothelial basement membrane: one at the level of the endothelial cells resulting in reduced adhesion and, thereby, increased penetrability of the monolayer; and secondly at the level of the T cells providing direct signals to the transmigrating cells.

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Perlecan regulates pericyte dynamics in the maintenance and repair of the blood–brain barrier

The Journal of Cell Biology ◽

10.1083/jcb.201807178 ◽

2019 ◽

Vol 218 (10) ◽

pp. 3506-3525 ◽

Cited By ~ 11

Author(s):

Kuniyuki Nakamura ◽

Tomoko Ikeuchi ◽

Kazuki Nara ◽

Craig S. Rhodes ◽

Peipei Zhang ◽

...

Keyword(s):

Ischemic Stroke ◽

Blood Brain Barrier ◽

Repair Process ◽

Artery Occlusion ◽

Basement Membranes ◽

Brain Barrier ◽

Integrin Α5β1 ◽

Ischemic Lesion ◽

Maintenance And Repair ◽

Blood Brain

Ischemic stroke causes blood–brain barrier (BBB) breakdown due to significant damage to the integrity of BBB components. Recent studies have highlighted the importance of pericytes in the repair process of BBB functions triggered by PDGFRβ up-regulation. Here, we show that perlecan, a major heparan sulfate proteoglycan of basement membranes, aids in BBB maintenance and repair through pericyte interactions. Using a transient middle cerebral artery occlusion model, we found larger infarct volumes and more BBB leakage in conditional perlecan (Hspg2)-deficient (Hspg2−/−-TG) mice than in control mice. Control mice showed increased numbers of pericytes in the ischemic lesion, whereas Hspg2−/−-TG mice did not. At the mechanistic level, pericytes attached to recombinant perlecan C-terminal domain V (perlecan DV, endorepellin). Perlecan DV enhanced the PDGF-BB–induced phosphorylation of PDGFRβ, SHP-2, and FAK partially through integrin α5β1 and promoted pericyte migration. Perlecan therefore appears to regulate pericyte recruitment through the cooperative functioning of PDGFRβ and integrin α5β1 to support BBB maintenance and repair following ischemic stroke.

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Human Apolipoprotein E ε4 Expression Impairs Cerebral Vascularization and Blood—Brain Barrier Function in Mice

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2014.172 ◽

2014 ◽

Vol 35 (1) ◽

pp. 86-94 ◽

Cited By ~ 77

Author(s):

Wael Alata ◽

Yue Ye ◽

Isabelle St-Amour ◽

Milène Vandal ◽

Frédéric Calon

Keyword(s):

Apolipoprotein E ◽

Blood Brain Barrier ◽

Apoe Genotype ◽

Brain Perfusion ◽

Basement Membranes ◽

Brain Barrier ◽

Brain Capillaries ◽

Human Apolipoprotein ◽

Blood Brain ◽

And Function

Human apolipoprotein E ( APOE) exists in three isoforms ε2, ε3, and ε4, of which APOE4 is the main genetic risk factor of Alzheimer's disease (AD). As cerebrovascular defects are associated with AD, we tested whether APOE genotype has an impact on the integrity and function of the blood—brain barrier (BBB) in human APOE-targeted replacement mice. Using the quantitative in situ brain perfusion technique, we first found lower (13.0% and 17.0%) brain transport coefficient (Clup) of [3H]-diazepam in APOE4 mice at 4 and 12 months, compared with APOE2 and APOE3 mice, reflecting a decrease in cerebral vascularization. Accordingly, results from immunohistofluorescence experiments revealed a structurally reduced cerebral vascularization (26% and 38%) and thinner basement membranes (30% and 35%) in 12-month-old APOE4 mice compared with APOE2 and APOE3 mice, suggesting vascular atrophy. In addition, APOE4 mice displayed a 29% reduction in [3H]-d-glucose transport through the BBB compared with APOE2 mice without significant changes in the expression of its transporter GLUT1 in brain capillaries. However, an increase of 41.3% of receptor for advanced glycation end products (RAGE) was found in brain capillaries of 12-month-old APOE4 mice. In conclusion, profound divergences were observed between APOE genotypes at the cerebrovascular interface, suggesting that APOE4-induced BBB anomalies may contribute to AD development.

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The Structure and Function of the Glycocalyx and Its Connection With Blood-Brain Barrier

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.739699 ◽

2021 ◽

Vol 15 ◽

Author(s):

Jing Jin ◽

Fuquan Fang ◽

Wei Gao ◽

Hanjian Chen ◽

Jiali Wen ◽

...

Keyword(s):

Endothelial Cells ◽

Blood Brain Barrier ◽

Cell Activation ◽

Vascular Endothelial Cells ◽

Neurological Diseases ◽

Basement Membranes ◽

Brain Barrier ◽

Endothelial Glycocalyx ◽

Vascular Endothelial ◽

Blood Brain

The vascular endothelial glycocalyx is a dense, bush-like structure that is synthesized and secreted by endothelial cells and evenly distributed on the surface of vascular endothelial cells. The blood-brain barrier (BBB) is mainly composed of pericytes endothelial cells, glycocalyx, basement membranes, and astrocytes. The glycocalyx in the BBB plays an indispensable role in many important physiological functions, including vascular permeability, inflammation, blood coagulation, and the synthesis of nitric oxide. Damage to the fragile glycocalyx can lead to increased permeability of the BBB, tissue edema, glial cell activation, up-regulation of inflammatory chemokines expression, and ultimately brain tissue damage, leading to increased mortality. This article reviews the important role that glycocalyx plays in the physiological function of the BBB. The review may provide some basis for the research direction of neurological diseases and a theoretical basis for the diagnosis and treatment of neurological diseases.

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