Cerebral microvascular endothelium and the pathogenesis of neurodegenerative diseases

2011 ◽  
Vol 13 ◽  
Author(s):  
Paula Grammas ◽  
Joseph Martinez ◽  
Bradley Miller
Keyword(s):  
Endothelial Cells ◽  
Dynamic Properties ◽  
Early Event ◽  
High Concentration ◽  
Microvascular Endothelium ◽  
Leukocyte Transmigration ◽  
New Therapeutic Approaches ◽  
The Central Nervous System ◽  
Cerebrovascular Endothelial Cells ◽  
The Brain

Diseases of the central nervous system (CNS) pose a significant health challenge, but despite their diversity, they share many common features and mechanisms. For example, endothelial dysfunction has been implicated as a crucial event in the development of several CNS disorders, such as Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, multiple sclerosis, human immunodeficiency virus (HIV)-1-associated neurocognitive disorder and traumatic brain injury. Breakdown of the blood–brain barrier (BBB) as a result of disruption of tight junctions and transporters, leads to increased leukocyte transmigration and is an early event in the pathology of these disorders. The brain endothelium is highly reactive because it serves as both a source of, and a target for, inflammatory proteins and reactive oxygen species. BBB breakdown thus leads to neuroinflammation and oxidative stress, which are implicated in the pathogenesis of CNS disease. Furthermore, the physiology and pathophysiology of endothelial cells are closely linked to the functioning of their mitochondria, and mitochondrial dysfunction is another important mediator of disease pathology in the brain. The high concentration of mitochondria in cerebrovascular endothelial cells might account for the sensitivity of the BBB to oxidant stressors. Here, we discuss how greater understanding of the role of BBB function could lead to new therapeutic approaches for diseases of the CNS that target the dynamic properties of brain endothelial cells.

scholarly journals Role of endothelial nitric oxide synthase-derived nitric oxide in activation and dysfunction of cerebrovascular endothelial cells during early onsets of sepsis

2008 ◽  
Vol 295 (4) ◽  
pp. H1712-H1719 ◽  
Author(s):  
Osamu Handa ◽  
Jancy Stephen ◽  
Gediminas Cepinskas
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Nitric Oxide Synthase ◽  
Mass Flux ◽  
Oxidant Stress ◽  
Junction Protein ◽  
Cerebrovascular Endothelial Cells ◽  
Oxide Synthase ◽  
The Brain

Sepsis-associated encephalopathy is an early manifestation of sepsis, resulting in a diffuse dysfunction of the brain. Recently, nitric oxide (NO) has been proposed to be one of the key molecules involved in the modulation of inflammatory responses in the brain. The aim of this study was to assess the role of NO in cerebrovascular endothelial cell activation/dysfunction during the early onsets of sepsis. To this end, we employed an in vitro model of sepsis in which cultured mouse cerebrovascular endothelial cells (MCVEC) were challenged with blood plasma (20% vol/vol) obtained from sham or septic (feces-induced peritonitis, FIP; 6 h) mice. Exposing MCVEC to FIP plasma for 1 h resulted in increased production of reactive oxygen species and NO as assessed by intracellular oxidation of oxidant-sensitive fluorochrome, dihydrorhodamine 123 (DHR 123), and nitrosation of NO-specific probe, DAF-FM, respectively. The latter events were accompanied by dissociation of tight junction protein, occludin, from MCVEC cytoskeletal framework and a subsequent increase in FITC-dextran (3-kDa mol mass) flux across MCVEC grown on the permeable cell culture supports, whereas Evans blue-BSA (65-kDa mol mass) or FITC-dextran (10-kDa mol mass) flux were not affected. FIP plasma-induced oxidant stress, occludin rearrangement, and MCVEC permeability were effectively attenuated by antioxidant, 1-pyrrolidinecarbodithioic acid (PDTC; 0.5 mM), or interfering with nitric oxide synthase (NOS) activity [0.1 mM nitro-l-arginine methyl ester (l-NAME) or endothelial NOS (eNOS)-deficient MCVEC]. However, treatment of MCVEC with PDTC failed to interfere with NO production, suggesting that septic plasma-induced oxidant stress in MCVEC is primarily a NO-dependent event. Taken together, these data indicate that during early sepsis, eNOS-derived NO exhibits proinflammatory characteristics and contributes to the activation and dysfunction of cerebrovascular endothelial cells.

scholarly journals Foe or friend? Janus-faces of the neurovascular unit in the formation of brain metastases

2017 ◽  
Vol 38 (4) ◽  
pp. 563-587 ◽  
Author(s):  
Imola Wilhelm ◽  
Csilla Fazakas ◽  
Kinga Molnár ◽  
Attila G Végh ◽  
János Haskó ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Endothelial Cells ◽  
Neurovascular Unit ◽  
Malignant Cells ◽  
Metastasis Formation ◽  
Primary Tumors ◽  
Brain Vasculature ◽  
Metastatic Cells ◽  
The Central Nervous System ◽  
The Brain

Despite the potential obstacle represented by the blood–brain barrier for extravasating malignant cells, metastases are more frequent than primary tumors in the central nervous system. Not only tightly interconnected endothelial cells can hinder metastasis formation, other cells of the brain microenvironment (like astrocytes and microglia) can also be very hostile, destroying the large majority of metastatic cells. However, malignant cells that are able to overcome these harmful mechanisms may benefit from the shielding and even support provided by cerebral endothelial cells, astrocytes and microglia, rendering the brain a sanctuary site against anti-tumor strategies. Thus, cells of the neurovascular unit have a Janus-faced attitude towards brain metastatic cells, being both destructive and protective. In this review, we present the main mechanisms of brain metastasis formation, including those involved in extravasation through the brain vasculature and survival in the cerebral environment.

scholarly journals Cell to cell communication is an early event in glioblastoma

2020 ◽  
Author(s):  
Marta Portela ◽  
Teresa Mitchell ◽  
Sergio Casas-Tintó
Keyword(s):  
Cell Communication ◽  
Matrix Metalloproteases ◽  
Temporal Organization ◽  
Early Event ◽  
Cellular Interactions ◽  
Jnk Pathway ◽  
The Central Nervous System ◽  
Mediate Cell ◽  
Molecular Signals ◽  
The Brain

SummaryGlioblastoma (GB) is the most aggressive and lethal tumour of the central nervous system (CNS). GB cells proliferate rapidly and display a network of ultra-long tumour microtubes (TMs) that mediate cell to cell communication. GB TMs infiltrate into the brain, enwrap neurons and facilitate the depletion of Wingless (Wg)/WNT from the neighbouring neurons. GB cells establish a positive feedback loop including Wg signalling upregulation that activates the JNK pathway and matrix metalloproteases (MMPs), in turn, these signals promote TMs infiltration, GB progression and neuronal synapse loss and degeneration. Thus, cellular and molecular signals other than primary mutations emerge as central players of GB. Here we describe the temporal organization of the events that occur in GB. We define the progressive activation of JNK pathway signalling mediated by Grindelwald (Grnd) receptor, is caused by the ligand Eiger (Egr)/TNFα produced by the healthy tissue. We propose that cellular interactions of GB with the rest of the brain is an early event that precedes GB proliferation and expansion. We conclude that non-autonomous signals facilitate GB progression and contribute to the complexity and versatility of these incurable tumours.

scholarly journals Tight Junction Modulating Bioprobes for Drug Delivery System to the Brain: A Review

Pharmaceutics ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1236
Author(s):  
Keisuke Tachibana ◽  
Yumi Iwashita ◽  
Erika Wakayama ◽  
Itsuki Nishino ◽  
Taiki Nishikaji ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Central Nervous System ◽  
Endothelial Cells ◽  
Nervous System ◽  
Extracellular Fluid ◽  
Transport Systems ◽  
Brain Extracellular Fluid ◽  
The Central Nervous System ◽  
Polarized Transport ◽  
The Brain

The blood-brain barrier (BBB), which is composed of endothelial cells, pericytes, astrocytes, and neurons, separates the brain extracellular fluid from the circulating blood, and maintains the homeostasis of the central nervous system (CNS). The BBB endothelial cells have well-developed tight junctions (TJs) and express specific polarized transport systems to tightly control the paracellular movements of solutes, ions, and water. There are two types of TJs: bicellular TJs (bTJs), which is a structure at the contact of two cells, and tricellular TJs (tTJs), which is a structure at the contact of three cells. Claudin-5 and angulin-1 are important components of bTJs and tTJs in the brain, respectively. Here, we review TJ-modulating bioprobes that enable drug delivery to the brain across the BBB, focusing on claudin-5 and angulin-1.

scholarly journals The brain’sglymphatic system:physiological anatomy and clinical perspectives

2018 ◽  
Vol 10 (4) ◽  
pp. 94-100 ◽  
Author(s):  
V. N. Nikolenko ◽  
M. V. Oganesyan ◽  
N. N. Yakhno ◽  
E. A. Orlov ◽  
E. E. Porubayeva ◽  
...  
Keyword(s):  
Interstitial Fluid ◽  
Cerebral Arteries ◽  
Lymphatic Vessels ◽  
Circulatory System ◽  
Brain Parenchyma ◽  
Special Role ◽  
Close Link ◽  
New Therapeutic Approaches ◽  
The Central Nervous System ◽  
The Brain

The recently discovered glymphatic system (GS) ensures the efficient clearance of interstitial fluid and soluble compounds from the central nervous system into cerebrospinal fluid (CSF), which compensates for the lack of conventional lymphatic vessels in the brain parenchyma. This unique anatomical and physiological phenomenon had been unknown until 2012. GS lacks inherent proper vessels Р the current of CSF and interstitial fluid is carried out directly inside the arterial walls (the perivascular pathway) or near the walls of the cerebral arteries and veins (the paravascular pathway). Current biorheological technologies could establish a special role of aquaporin-4 in the filtration of CSF and interstitial fluid. The close link between GS and the CSF circulatory system allows the established views on fluid dynamics within the brain to be reconsidered. The discovery of GS can contribute to our understanding of the pathogenesis of increased intracranial pressure and neurodegenerative diseases, as well as to the elaboration of new therapeutic approaches to their treatment.

scholarly journals Cryptococcus neoformans Promotes Its Transmigration into the Central Nervous System by Inducing Molecular and Cellular Changes in Brain Endothelial Cells

2013 ◽  
Vol 81 (9) ◽  
pp. 3139-3147 ◽  
Author(s):  
Kiem Vu ◽  
Richard A. Eigenheer ◽  
Brett S. Phinney ◽  
Angie Gelli
Keyword(s):  
Central Nervous System ◽  
Endothelial Cells ◽  
Nervous System ◽  
Human Brain ◽  
Cryptococcus Neoformans ◽  
Brain Endothelial Cells ◽  
Brain Endothelium ◽  
Content Type ◽  
The Central Nervous System ◽  
The Brain

ABSTRACTCryptococcusspp. cause fungal meningitis, a life-threatening infection that occurs predominately in immunocompromised individuals. In order forCryptococcus neoformansto invade the central nervous system (CNS), it must first penetrate the brain endothelium, also known as the blood-brain barrier (BBB). Despite the importance of the interrelation betweenC. neoformansand the brain endothelium in establishing CNS infection, very little is known about this microenvironment. Here we sought to resolve the cellular and molecular basis that defines the fungal-BBB interface during cryptococcal attachment to, and internalization by, the human brain endothelium. In order to accomplish this by a systems-wide approach, the proteomic profile of human brain endothelial cells challenged withC. neoformanswas resolved using a label-free differential quantitative mass spectrometry method known as spectral counting (SC). Here, we demonstrate that as brain endothelial cells associate with, and internalize, cryptococci, they upregulate the expression of several proteins involved with cytoskeleton, metabolism, signaling, and inflammation, suggesting that they are actively signaling and undergoing cytoskeleton remodeling via annexin A2, S100A10, transgelin, and myosin. Transmission electronic microscopy (TEM) analysis demonstrates dramatic structural changes in nuclei, mitochondria, the endoplasmic reticulum (ER), and the plasma membrane that are indicative of cell stress and cell damage. The translocation of HMGB1, a marker of cell injury, the downregulation of proteins that function in transcription, energy production, protein processing, and the upregulation of cyclophilin A further support the notion thatC. neoformanselicits changes in brain endothelial cells that facilitate the migration of cryptococci across the BBB and ultimately induce endothelial cell necrosis.

scholarly journals Cryptococcal Yeast Cells Invade the Central Nervous System via Transcellular Penetration of the Blood-Brain Barrier

2004 ◽  
Vol 72 (9) ◽  
pp. 4985-4995 ◽  
Author(s):  
Yun C. Chang ◽  
Monique F. Stins ◽  
Michael J. McCaffery ◽  
Georgina F. Miller ◽  
Dan R. Pare ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Endothelial Cells ◽  
Nervous System ◽  
Blood Brain Barrier ◽  
Yeast Cells ◽  
Brain Barrier ◽  
Blood Brain ◽  
The Central Nervous System ◽  
The Brain

ABSTRACT Cryptococcal meningoencephalitis develops as a result of hematogenous dissemination of inhaled Cryptococcus neoformans from the lung to the brain. The mechanism(s) by which C. neoformans crosses the blood-brain barrier (BBB) is a key unresolved issue in cryptococcosis. We used both an in vivo mouse model and an in vitro model of the human BBB to investigate the cryptococcal association with and traversal of the BBB. Exposure of human brain microvascular endothelial cells (HBMEC) to C. neoformans triggered the formation of microvillus-like membrane protrusions within 15 to 30 min. Yeast cells of C. neoformans adhered to and were internalized by the HBMEC, and they crossed the HBMEC monolayers via a transcellular pathway without affecting the monolayer integrity. The histopathology of mouse brains obtained after intravenous injection of C. neoformans showed that the yeast cells either were associated with endothelial cells or escaped from the brain capillary vessels into the neuropil by 3 h. C. neoformans was found in the brain parenchyma away from the vessels by 22 h. Association of C. neoformans with the choroid plexus, however, was not detected during up to 10 days of observation. Our findings indicate that C. neoformans cells invade the central nervous system by transcellular crossing of the endothelium of the BBB.

scholarly journals Auraptene Enhances Junction Assembly in Cerebrovascular Endothelial Cells by Promoting Resilience to Mitochondrial Stress through Activation of Antioxidant Enzymes and mtUPR

Antioxidants ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 475
Author(s):  
Min Joung Lee ◽  
Yunseon Jang ◽  
Jiebo Zhu ◽  
Eunji Namgung ◽  
Dahyun Go ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Antioxidant Enzymes ◽  
Vascular Endothelial ◽  
Unfolded Protein ◽  
Vascular Endothelial Cadherin ◽  
Junctional Proteins ◽  
Cerebrovascular Endothelial Cells ◽  
Protein Response ◽  
The Brain ◽  
Mitochondrial Unfolded Protein Response

Junctional proteins in cerebrovascular endothelial cells are essential for maintaining the barrier function of the blood-brain barrier (BBB), thus protecting the brain from the infiltration of pathogens. The present study showed that the potential therapeutic natural compound auraptene (AUR) enhances junction assembly in cerebrovascular endothelial cells by inducing antioxidant enzymes and the mitochondrial unfolded protein response (mtUPR). Treatment of mouse cerebrovascular endothelial cells with AUR enhanced the expression of junctional proteins, such as occludin, zonula occludens-1 (ZO-1) and vascular endothelial cadherin (VE-cadherin), by increasing the levels of mRNA encoding antioxidant enzymes. AUR treatment also resulted in the depolarization of mitochondrial membrane potential and activation of mtUPR. The ability of AUR to protect against ischemic conditions was further assessed using cells deprived of oxygen and glucose. Pretreatment of these cells with AUR protected against damage to junctional proteins, including occludin, claudin-5, ZO-1 and VE-cadherin, accompanied by a stress resilience response regulated by levels of ATF5, LONP1 and HSP60 mRNAs. Collectively, these results indicate that AUR promotes resilience against oxidative stress and improves junction assembly, suggesting that AUR may help maintain intact barriers in cerebrovascular endothelial cells.

Endotoxin Alteration of the Mucopolysaccharide Blood Vessel Coating in Rats

1974 ◽  
Vol 32 ◽  
pp. 148-149
Author(s):  
D. E. Philpott ◽  
A. Takahashi
Keyword(s):  
Skeletal Muscle ◽  
Endothelial Cells ◽  
Salivary Gland ◽  
Carotid Artery ◽  
Basement Membrane ◽  
Coronary Vessels ◽  
Ruthenium Red ◽  
E Coli ◽  
Old Rats ◽  
The Brain

Two month, eight month and two year old rats were treated with 10 or 20 mg/kg of E. Coli endotoxin I. P. The eight month old rats proved most resistant to the endotoxin. During fixation the aorta, carotid artery, basil arartery of the brain, coronary vessels of the heart, inner surfaces of the heart chambers, heart and skeletal muscle, lung, liver, kidney, spleen, brain, retina, trachae, intestine, salivary gland, adrenal gland and gingiva were treated with ruthenium red or alcian blue to preserve the mucopolysaccharide (MPS) coating. Five, 8 and 24 hrs of endotoxin treatment produced increasingly marked capillary damage, disappearance of the MPS coating, edema, destruction of endothelial cells and damage to the basement membrane in the liver, kidney and lung.

Presence of antibody in virus-infected brain cells of SSPE ferrets

1983 ◽  
Vol 41 ◽  
pp. 804-805
Author(s):  
Hannah R. Brown ◽  
Tammy L. Donato ◽  
Halldor Thormar
Keyword(s):  
Measles Virus ◽  
Plasma Cells ◽  
Subacute Sclerosing Panencephalitis ◽  
Protein A ◽  
Neutralizing Antibody ◽  
Brain Cells ◽  
Antibody Titers ◽  
A Cell ◽  
The Central Nervous System ◽  
The Brain

Measles virus specific immunoglobulin G (IgG) has been found in the brains of patients with subacute sclerosing panencephalitis (SSPE), a slowly progressing disease of the central nervous system (CNS) in children. IgG/albumin ratios indicate that the antibodies are synthesized within the CNS. Using the ferret as an animal model to study the disease, we have been attempting to localize the Ig's in the brains of animals inoculated with a cell associated strain of SSPE. In an earlier report, preliminary results using Protein A conjugated to horseradish peroxidase (PrAPx) (Dynatech Diagnostics Inc., South Windham, ME.) to detect antibodies revealed the presence of immunoglobulin mainly in antibody-producing plasma cells in inflammatory lesions and not in infected brain cells.In the present experiment we studied the brain of an SSPE ferret with neutralizing antibody titers of 1:1024 in serum and 1:512 in CSF at time of sacrifice 7 months after i.c. inoculation with SSPE measles virus-infected cells. The animal was perfused with saline and portions of the brain and spinal cord were immersed in periodate-lysine-paraformaldehyde (P-L-P) fixative. The ferret was not perfused with fixative because parts of the brain were used for virus isolation.

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