Endothelial Dysfunction in the Brain

Neurological Sequelae ◽

Cerebrovascular Complications ◽

Hemostatic Markers ◽

Tract Infections ◽

And Function ◽

The Brain ◽

Major Target

The Coronavirus disease 2019 (COVID)-19 pandemic has already affected millions worldwide, with a current mortality rate of 2.2%. While it is well-established that severe acute respiratory syndrome-coronavirus-2 causes upper and lower respiratory tract infections, a number of neurological sequelae have now been reported in a large proportion of cases. Additionally, the disease causes arterial and venous thromboses including pulmonary embolism, myocardial infarction, and a significant number of cerebrovascular complications. The increasing incidence of large vessel ischemic strokes as well as intracranial hemorrhages, frequently in younger individuals, and associated with increased morbidity and mortality, has raised questions as to why the brain is a major target of the disease. COVID-19 is characterized by hypercoagulability with alterations in hemostatic markers including high D-dimer levels, which are a prognosticator of poor outcome. Together with findings of fibrin-rich microthrombi, widespread extracellular fibrin deposition in affected various organs and hypercytokinemia, this suggests that COVID-19 is more than a pulmonary viral infection. Evidently, COVID-19 is a thrombo-inflammatory disease. Endothelial cells that constitute the lining of blood vessels are the primary targets of a thrombo-inflammatory response, and severe acute respiratory syndrome coronavirus 2 also directly infects endothelial cells through the ACE2 (angiotensin-converting enzyme 2) receptor. Being highly heterogeneous in their structure and function, differences in the endothelial cells may govern the susceptibility of organs to COVID-19. Here, we have explored how the unique characteristics of the cerebral endothelium may be the underlying reason for the increased rates of cerebrovascular pathology associated with COVID-19.

Severe Acute Respiratory Syndrome Coronavirus Infection Causes Neuronal Death in the Absence of Encephalitis in Mice Transgenic for Human ACE2

Journal of Virology ◽

10.1128/jvi.00737-08 ◽

2008 ◽

Vol 82 (15) ◽

pp. 7264-7275 ◽

Cited By ~ 470

Author(s):

Jason Netland ◽

David K. Meyerholz ◽

Steven Moore ◽

Martin Cassell ◽

Stanley Perlman

Keyword(s):

Cell Receptor ◽

Neurological Sequelae ◽

Brain Infection ◽

Host Cell Receptor ◽

Coronavirus Infection ◽

The Brain ◽

Major Target

ABSTRACT Infection of humans with the severe acute respiratory syndrome coronavirus (SARS-CoV) results in substantial morbidity and mortality, with death resulting primarily from respiratory failure. While the lungs are the major site of infection, the brain is also infected in some patients. Brain infection may result in long-term neurological sequelae, but little is known about the pathogenesis of SARS-CoV in this organ. We previously showed that the brain was a major target organ for infection in mice that are transgenic for the SARS-CoV receptor (human angiotensin-converting enzyme 2). Herein, we use these mice to show that virus enters the brain primarily via the olfactory bulb, and infection results in rapid, transneuronal spread to connected areas of the brain. This extensive neuronal infection is the main cause of death because intracranial inoculation with low doses of virus results in a uniformly lethal disease even though little infection is detected in the lungs. Death of the animal likely results from dysfunction and/or death of infected neurons, especially those located in cardiorespiratory centers in the medulla. Remarkably, the virus induces minimal cellular infiltration in the brain. Our results show that neurons are a highly susceptible target for SARS-CoV and that only the absence of the host cell receptor prevents severe murine brain disease.

Differential Virological and Immunological Outcome of Severe Acute Respiratory Syndrome Coronavirus Infection in Susceptible and Resistant Transgenic Mice Expressing Human Angiotensin-Converting Enzyme 2

Journal of Virology ◽

10.1128/jvi.02272-08 ◽

2009 ◽

Vol 83 (11) ◽

pp. 5451-5465 ◽

Cited By ~ 24

Author(s):

Naoko Yoshikawa ◽

Tomoki Yoshikawa ◽

Terence Hill ◽

Cheng Huang ◽

Douglas M. Watts ◽

...

Keyword(s):

T Cells ◽

Angiotensin Converting Enzyme ◽

Viral Infection ◽

Inflammatory Responses ◽

Fatal Outcome ◽

Converting Enzyme ◽

Inflammatory Infiltrates ◽

ABSTRACT We previously reported that transgenic (Tg) mice expressing human angiotensin-converting enzyme 2 (hACE2), the receptor for severe acute respiratory syndrome coronavirus (SARS-CoV), were highly susceptible to SARS-CoV infection, which resulted in the development of disease of various severity and even death in some lineages. In this study, we further characterized and compared the pathogeneses of SARS-CoV infection in two of the most stable Tg lineages, AC70 and AC22, representing those susceptible and resistant to the lethal SARS-CoV infection, respectively. The kinetics of virus replication and the inflammatory responses within the lungs and brains, as well as the clinical and pathological outcomes, were assessed in each lineage. In addition, we generated information on lymphocyte subsets and mitogen-mediated proliferation of splenocytes. We found that while both lineages were permissive to SARS-CoV infection, causing elevated secretion of many inflammatory mediators within the lungs and brains, viral infection appeared to be more intense in AC70 than in AC22 mice, especially in the brain. Moreover, such infection was accompanied by a more profound immune suppression in the former, as evidenced by the extensive loss of T cells, compromised responses to concanavalin A stimulation, and absence of inflammatory infiltrates within the brain. We also found that CD8+ T cells were partially effective in attenuating the pathogenesis of SARS-CoV infection in lethality-resistant AC22 mice. Collectively, our data revealed a more intense viral infection and immunosuppression in AC70 mice than in AC22 mice, thereby providing us with an immunopathogenic basis for the fatal outcome of SARS-CoV infection in the AC70 mice.

Differential Expression of CD31 and Von Willebrand Factor on Endothelial Cells in Different Regions of the Human Brain: Potential Implications for Cerebral Malaria Pathogenesis

Brain Sciences ◽

10.3390/brainsci10010031 ◽

2020 ◽

Vol 10 (1) ◽

pp. 31 ◽

Cited By ~ 4

Author(s):

Smart Ikechukwu Mbagwu ◽

Luis Filgueira

Keyword(s):

Endothelial Cells ◽

Endothelial Cell ◽

Human Brain ◽

Expression Pattern ◽

Von Willebrand Factor ◽

Brain Regions ◽

And Function ◽

Von Willebrand ◽

Willebrand Factor ◽

Cerebral microvascular endothelial cells (CMVECs) line the vascular system of the brain and are the chief cells in the formation and function of the blood brain barrier (BBB). These cells are heterogeneous along the cerebral vasculature and any dysfunctional state in these cells can result in a local loss of function of the BBB in any region of the brain. There is currently no report on the distribution and variation of the CMVECs in different brain regions in humans. This study investigated microcirculation in the adult human brain by the characterization of the expression pattern of brain endothelial cell markers in different brain regions. Five different brain regions consisting of the visual cortex, the hippocampus, the precentral gyrus, the postcentral gyrus, and the rhinal cortex obtained from three normal adult human brain specimens were studied and analyzed for the expression of the endothelial cell markers: cluster of differentiation 31 (CD31) and von-Willebrand-Factor (vWF) through immunohistochemistry. We observed differences in the expression pattern of CD31 and vWF between the gray matter and the white matter in the brain regions. Furthermore, there were also regional variations in the pattern of expression of the endothelial cell biomarkers. Thus, this suggests differences in the nature of vascularization in various regions of the human brain. These observations also suggest the existence of variation in structure and function of different brain regions, which could reflect in the pathophysiological outcomes in a diseased state.

How Hormones Influence Composition and Physiological Function of the Brain-Blood Barrier

Physiological Research ◽

10.33549/physiolres.933110 ◽

2015 ◽

pp. S259-S264 ◽

Cited By ~ 2

Author(s):

R. HAMPL ◽

M. BIČÍKOVÁ ◽

L. SOSVOROVÁ

Keyword(s):

Endothelial Cells ◽

Tight Junctions ◽

Blood Brain Barrier ◽

Physiological Function ◽

Brain Barrier ◽

Major Protein ◽

Other Substances ◽

And Function ◽

Protein Transporters ◽

Hormones exert many actions in the brain. Their access and effects in the brain are regulated by the blood-brain barrier (BBB). Hormones as other substances may enter the brain and vice versa either by paracellular way requiring breaching tight junctions stitching the endothelial cells composing the BBB, or by passage through the cells (transcellular way). Hormones influence both ways through their receptors, both membrane and intracellular, present on/in the BBB. In the review the main examples are outlined how hormones influence the expression and function of proteins forming the tight junctions, as well as how they regulate expression and function of major protein transporters mediating transport of various substances including hormone themselves.

Lethal Infection of K18-hACE2 Mice Infected with Severe Acute Respiratory Syndrome Coronavirus

Journal of Virology ◽

10.1128/jvi.02012-06 ◽

2006 ◽

Vol 81 (2) ◽

pp. 813-821 ◽

Cited By ~ 278

Author(s):

Paul B. McCray ◽

Lecia Pewe ◽

Christine Wohlford-Lenane ◽

Melissa Hickey ◽

Lori Manzel ◽

...

Keyword(s):

Economic Losses ◽

Potential Threat ◽

Antiviral Therapies ◽

Brain Infection ◽

Cytokines And Chemokines ◽

Lethal Infection ◽

Novel Coronavirus ◽

ABSTRACT The severe acute respiratory syndrome (SARS), caused by a novel coronavirus (SARS-CoV), resulted in substantial morbidity, mortality, and economic losses during the 2003 epidemic. While SARS-CoV infection has not recurred to a significant extent since 2003, it still remains a potential threat. Understanding of SARS and development of therapeutic approaches have been hampered by the absence of an animal model that mimics the human disease and is reproducible. Here we show that transgenic mice that express the SARS-CoV receptor (human angiotensin-converting enzyme 2 [hACE2]) in airway and other epithelia develop a rapidly lethal infection after intranasal inoculation with a human strain of the virus. Infection begins in airway epithelia, with subsequent alveolar involvement and extrapulmonary virus spread to the brain. Infection results in macrophage and lymphocyte infiltration in the lungs and upregulation of proinflammatory cytokines and chemokines in both the lung and the brain. This model of lethal infection with SARS-CoV should be useful for studies of pathogenesis and for the development of antiviral therapies.

Spike Proteins of SARS-CoV-2 Induce Pathological Changes in Molecular Delivery and Metabolic Function in the Brain Endothelial Cells

Viruses ◽

10.3390/v13102021 ◽

2021 ◽

Vol 13 (10) ◽

pp. 2021

Author(s):

Eun Seon Kim ◽

Min-Tae Jeon ◽

Kyu-Sung Kim ◽

Suji Lee ◽

Suji Kim ◽

...

Keyword(s):

Endothelial Cells ◽

Host Cells ◽

Spike Protein ◽

Metabolic Function ◽

Brain Endothelial Cells ◽

Functional Deficits ◽

Molecular Delivery ◽

Pathological Mechanism ◽

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes the coronavirus disease (COVID-19), is currently infecting millions of people worldwide and is causing drastic changes in people’s lives. Recent studies have shown that neurological symptoms are a major issue for people infected with SARS-CoV-2. However, the mechanism through which the pathological effects emerge is still unclear. Brain endothelial cells (ECs), one of the components of the blood–brain barrier, are a major hurdle for the entry of pathogenic or infectious agents into the brain. They strongly express angiotensin converting enzyme 2 (ACE2) for its normal physiological function, which is also well-known to be an opportunistic receptor for SARS-CoV-2 spike protein, facilitating their entry into host cells. First, we identified rapid internalization of the receptor-binding domain (RBD) S1 domain (S1) and active trimer (Trimer) of SARS-CoV-2 spike protein through ACE2 in brain ECs. Moreover, internalized S1 increased Rab5, an early endosomal marker while Trimer decreased Rab5 in the brain ECs. Similarly, the permeability of transferrin and dextran was increased in S1 treatment but decreased in Trimer, respectively. Furthermore, S1 and Trimer both induced mitochondrial damage including functional deficits in mitochondrial respiration. Overall, this study shows that SARS-CoV-2 itself has toxic effects on the brain ECs including defective molecular delivery and metabolic function, suggesting a potential pathological mechanism to induce neurological signs in the brain.

Brain Invasion by Mouse Hepatitis Virus Depends on Impairment of Tight Junctions and Beta Interferon Production in Brain Microvascular Endothelial Cells

Journal of Virology ◽

10.1128/jvi.01501-15 ◽

2015 ◽

Vol 89 (19) ◽

pp. 9896-9908 ◽

Cited By ~ 35

Author(s):

Christian Bleau ◽

Aveline Filliol ◽

Michel Samson ◽

Lucie Lamontagne

Keyword(s):

Endothelial Cells ◽

Tight Junctions ◽

Hepatitis Virus ◽

Mouse Hepatitis Virus ◽

Microvascular Endothelial Cells ◽

Brain Microvascular Endothelial Cells ◽

Brain Invasion ◽

Beta Interferon ◽

ABSTRACTCoronaviruses (CoVs) have shown neuroinvasive properties in humans and animals secondary to replication in peripheral organs, but the mechanism of neuroinvasion is unknown. The major aim of our work was to evaluate the ability of CoVs to enter the central nervous system (CNS) through the blood-brain barrier (BBB). Using the highly hepatotropic mouse hepatitis virus type 3 (MHV3), its attenuated variant, 51.6-MHV3, which shows low tropism for endothelial cells, and the weakly hepatotropic MHV-A59 strain from the murine coronavirus group, we investigated the virus-induced dysfunctions of BBBin vivoand in brain microvascular endothelial cells (BMECs)in vitro. We report here a MHV strain-specific ability to cross the BBB during acute infection according to their virulence for liver. Brain invasion was observed only in MHV3-infected mice and correlated with enhanced BBB permeability associated with decreased expression of zona occludens protein 1 (ZO-1), VE-cadherin, and occludin, but not claudin-5, in the brain or in cultured BMECs. BBB breakdown in MHV3 infection was not related to production of barrier-dysregulating inflammatory cytokines or chemokines by infected BMECs but rather to a downregulation of barrier protective beta interferon (IFN-β) production. Our findings highlight the importance of IFN-β production by infected BMECs in preserving BBB function and preventing access of blood-borne infectious viruses to the brain.IMPORTANCECoronaviruses (CoVs) infect several mammals, including humans, and are associated with respiratory, gastrointestinal, and/or neurological diseases. There is some evidence that suggest that human respiratory CoVs may show neuroinvasive properties. Indeed, the severe acute respiratory syndrome coronavirus (SARS-CoV), causing severe acute respiratory syndrome, and the CoVs OC43 and 229E were found in the brains of SARS patients and multiple sclerosis patients, respectively. These findings suggest that hematogenously spread CoVs may gain access to the CNS at the BBB level. Herein we report for the first time that CoVs exhibit the ability to cross the BBB according to strain virulence. BBB invasion by CoVs correlates with virus-induced disruption of tight junctions on BMECs, leading to BBB dysfunction and enhanced permeability. We provide evidence that production of IFN-β by BMECs during CoV infection may prevent BBB breakdown and brain viral invasion.

Endotoxin Alteration of the Mucopolysaccharide Blood Vessel Coating in Rats

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100050755 ◽

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 ◽

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.

Ultrastructure of developing visual cortical synapses in the cat superior colliculus

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100085083 ◽

1991 ◽

Vol 49 ◽

pp. 156-157

Author(s):

Caroline A. Miller ◽

Laura L. Bruce

Keyword(s):

Superior Colliculus ◽

Phosphate Buffer ◽

Receptive Fields ◽

Visual Cortical Area ◽

Cortical Synapses ◽

Visual Cortical ◽

And Function ◽

Phosphate Buffered Saline ◽

The Brain ◽

Cat Superior Colliculus

The first visual cortical axons arrive in the cat superior colliculus by the time of birth. Adultlike receptive fields develop slowly over several weeks following birth. The developing cortical axons go through a sequence of changes before acquiring their adultlike morphology and function. To determine how these axons interact with neurons in the colliculus, cortico-collicular axons were labeled with biocytin (an anterograde neuronal tracer) and studied with electron microscopy.Deeply anesthetized animals received 200-500 nl injections of biocytin (Sigma; 5% in phosphate buffer) in the lateral suprasylvian visual cortical area. After a 24 hr survival time, the animals were deeply anesthetized and perfused with 0.9% phosphate buffered saline followed by fixation with a solution of 1.25% glutaraldehyde and 1.0% paraformaldehyde in 0.1M phosphate buffer. The brain was sectioned transversely on a vibratome at 50 μm. The tissue was processed immediately to visualize the biocytin.

Assembly and Activation of the Intrinsic Fibrinolytic Pathway on the Surface of Human Endothelial Cells in Culture

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649800 ◽

1995 ◽

Vol 74 (02) ◽

pp. 698-703 ◽

Cited By ~ 29

Author(s):

Catherine Lenich ◽

Ralph Pannell ◽

Victor Gurewich

Keyword(s):

Endothelial Cells ◽

Umbilical Vein ◽

Factor Xii ◽

Plasminogen Activation ◽

High Molecular Weight Kininogen ◽

Human Endothelial Cells ◽

Intrinsic Pathway ◽

Local Fibrinolysis ◽

Umbilical Vein Endothelial Cells ◽

And Function

SummaryFactor XII has long been implicated in the intrinsic pathway of fibrinolysis, but the mechanism by which it triggers plasminogen activation and targets fibrinolysis has not been established. In the present study, the assembly and function of activated Factor XII (F.XIIa), prourokinase (pro-u-PA), high molecular weight kininogen (H-kininogen), and prekallikrein on human umbilical vein endothelial cells (HUVEC) was investigated. 125I-prekallikrein was shown to bind to HUVEC via receptor-bound H-kininogen in the presence of 50 μM ZnCl2. After the addition of F.XIIa, 78% of the 125I-prekallikrein initially bound to HUVEC was converted to 125I-kallikrein. However, only 6% of the HUVEC-bound 125I-pro-u-PA was thereby activated. This discrepancy was shown to be related to rapid dissociation (>50% within 15 min) of prekallikrein/kallikrein, but not pro-u-PA, from HUVEC. Increasing the level of cell-bound kallikrein increased the portion of cell-bound pro-u-PA activated, indicating that their co-localization was important for this pathway. Finally, F.XIIa was shown to trigger plasminogen activation on HUVEC via this pathway. This assembly of reactants on the endothelium suggests a mechanism whereby local fibrinolysis may be triggered by blood coagulation.