scholarly journals Tight Junctions of the Neurovascular Unit

2021 ◽  
Vol 14 ◽  
Author(s):  
Natalie Hudson ◽  
Matthew Campbell
Keyword(s):  
Endothelial Cells ◽  
Tight Junction ◽  
Tight Junctions ◽  
Neurovascular Unit ◽  
Interacting Proteins ◽  
Blood Retinal Barrier ◽  
Tight Junction Complex ◽  
Retinal Pathology ◽  
Neural Tissues ◽  
The Brain

The homeostatic balance of the brain and retina is maintained by the presence of the blood-brain and inner blood-retinal barrier (BBB/iBRB, respectively) which are highly specialized barriers. Endothelial cells forming the lining of these blood vessels are interconnected by the presence of tight junctions which form the BBB and iBRB. These tight junctions, formed of numerous interacting proteins, enable the entry of molecules into neural tissues while restricting the entry of harmful material such as anaphylatoxins, bacteria and viruses. If the tight junction complex becomes dysregulated due to changes in expression levels of one or more of the components, this can have detrimental effects leading to brain and retinal pathology.

Abstract MP17: Upregulating E2F1 Mitigates Senescence-Associated Phenotypes in Cultured Primary Endothelial Cells

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Michael E Maniskas ◽  
Yun-ju Lai ◽  
Sean P Marrelli ◽  
Louise D McCullough ◽  
Jose F Moruno-manchon
Keyword(s):  
Endothelial Cells ◽  
Vascular Endothelial Cells ◽  
Neurovascular Unit ◽  
Glucose Deprivation ◽  
Cerebral Hypoperfusion ◽  
Aged Mouse ◽  
Aged Mice ◽  
Brain Vasculature ◽  
Bilateral Carotid ◽  
The Brain

Vascular contributions to cognitive impairment and dementia (VCID) includes multiple disorders that are identified by cognitive deficits secondary to cerebrovascular pathology. The risk of VCID is higher in people after the age of 70, and, currently, there is no effective treatment. Vascular endothelial cells (VEC) are critical components of the brain vasculature and neurovascular unit and their health is vital to the capacity of the brain vasculature to respond to stressors. However, aged VEC may enter an irreversible replicative-arrest state (senescence), which has been associated with dementia. E2F transcription factor 1 (E2F1) regulates cell cycle progression and DNA damage repair. Importantly, E2F1 deficiency is associated with cell senescence. We hypothesized that E2F1 downregulation contributes to senescence in the cerebral endothelium during aging. We used cultured primary VEC from young (4-months old, mo) and aged (18-mo) male and female mice for RNA sequencing, plasmid-based gene delivery, high-resolution microscopy, and (4-, 12-, and 18-mo) mice of the bilateral carotid artery stenosis (BCAS) model, which produces chronic cerebral hypoperfusion and recapitulates some of the features seen in patients with VCID. We found that overexpression of E2F1 reduced the levels of senescence-associated phenotypes in cultured VEC from young mice that were exposed to oxygen and glucose deprivation (p<0.001), which induces endothelial senescence. Our RNA seq data showed that the expression of E2f1 was reduced (~40%) in cultured primary VEC from aged mouse brains compared with young cells (p<0.001). E2F1 levels were reduced in the brains of aged mice. Interestingly, we found sex differences in E2F1 levels, with less protein levels (~30%) in males vs females (p<0.05), independently of age. Also, aged BCAS mice (1 month after surgery) had more severe senescence phenotypes, reduced cerebral blood flow, and worse memory deficits compared with control mice (p<0.05). The effect of BCAS was more prominent in aged mice compared with younger (4- and 12-mo) mice. In conclusion , our study identifies E2F1 as a potential regulator of endothelial senescence in mice and highlights the contribution of aging as an important factor in losing endothelial resilience.

scholarly journals Modulating the Blood-Brain Barrier by Light Stimulation of Molecular-Targeted Nanoparticles

2020 ◽  
Author(s):  
Xiaoqing Li ◽  
Vamsidhara Vemireddy ◽  
Qi Cai ◽  
Hejian Xiong ◽  
Peiyuan Kang ◽  
...  
Keyword(s):  
Tight Junction ◽  
Tight Junctions ◽  
Blood Brain Barrier ◽  
Therapeutic Interventions ◽  
Brain Barrier ◽  
Light Stimulation ◽  
Targeted Nanoparticles ◽  
Blood Brain ◽  
The Brain ◽  
Stimulation Of

AbstractThe blood-brain barrier (BBB) tightly regulates the entry of molecules into the brain by tight junctions that seals the paracellular space and receptor-mediated transcytosis. It remains elusive to selectively modulate these mechanisms and to overcome BBB without significant neurotoxicity. Here we report that light stimulation of tight junction-targeted plasmonic nanoparticles selectively opens up the paracellular route to allow diffusion through the compromised tight junction and into the brain parenchyma. The BBB modulation does not impair vascular dynamics and associated neurovascular coupling, or cause significant neural injury. It further allows antibody and adeno-associated virus delivery into local brain regions. This novel method offers the first evidence of selectively modulating BBB tight junctions and opens new avenues for therapeutic interventions in the central nervous system.One Sentence SummaryGentle stimulation of molecular-targeted nanoparticles selectively opens up the paracellular pathway and allows macromolecules and gene therapy vectors into the brain.

scholarly journals Direct Current Stimulation Disrupts Endothelial Glycocalyx and Tight Junctions of the Blood-Brain Barrier in vitro

2021 ◽  
Vol 9 ◽  
Author(s):  
Yifan Xia ◽  
Yunfei Li ◽  
Wasem Khalid ◽  
Marom Bikson ◽  
Bingmei M. Fu
Keyword(s):  
Endothelial Cells ◽  
Tight Junction ◽  
Tight Junctions ◽  
Blood Brain Barrier ◽  
Direct Current ◽  
Endothelial Glycocalyx ◽  
Microvascular Endothelial Cells ◽  
Bbb Permeability

Transcranial direct current stimulation (tDCS) is a non-invasive physical therapy to treat many psychiatric disorders and to enhance memory and cognition in healthy individuals. Our recent studies showed that tDCS with the proper dosage and duration can transiently enhance the permeability (P) of the blood-brain barrier (BBB) in rat brain to various sized solutes. Based on the in vivo permeability data, a transport model for the paracellular pathway of the BBB also predicted that tDCS can transiently disrupt the endothelial glycocalyx (EG) and the tight junction between endothelial cells. To confirm these predictions and to investigate the structural mechanisms by which tDCS modulates P of the BBB, we directly quantified the EG and tight junctions of in vitro BBB models after DCS treatment. Human cerebral microvascular endothelial cells (hCMECs) and mouse brain microvascular endothelial cells (bEnd3) were cultured on the Transwell filter with 3 μm pores to generate in vitro BBBs. After confluence, 0.1–1 mA/cm2 DCS was applied for 5 and 10 min. TEER and P to dextran-70k of the in vitro BBB were measured, HS (heparan sulfate) and hyaluronic acid (HA) of EG was immuno-stained and quantified, as well as the tight junction ZO-1. We found disrupted EG and ZO-1 when P to dextran-70k was increased and TEER was decreased by the DCS. To further investigate the cellular signaling mechanism of DCS on the BBB permeability, we pretreated the in vitro BBB with a nitric oxide synthase (NOS) inhibitor, L-NMMA. L-NMMA diminished the effect of DCS on the BBB permeability by protecting the EG and reinforcing tight junctions. These in vitro results conform to the in vivo observations and confirm the model prediction that DCS can disrupt the EG and tight junction of the BBB. Nevertheless, the in vivo effects of DCS are transient which backup its safety in the clinical application. In conclusion, our current study directly elucidates the structural and signaling mechanisms by which DCS modulates the BBB permeability.

Modulation of tight junction structure in blood-brain barrier endothelial cells. Effects of tissue culture, second messengers and cocultured astrocytes

1994 ◽  
Vol 107 (5) ◽  
pp. 1347-1357 ◽  
Author(s):  
H. Wolburg ◽  
J. Neuhaus ◽  
U. Kniesel ◽  
B. Krauss ◽  
E.M. Schmid ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tight Junction ◽  
Tight Junctions ◽  
Blood Brain Barrier ◽  
Barrier Function ◽  
Primary Cultures ◽  
Brain Barrier ◽  
Brain Endothelial Cells ◽  
Blood Brain ◽  
Camp Levels

Tight junctions between endothelial cells of brain capillaries are the most important structural elements of the blood-brain barrier. Cultured brain endothelial cells are known to loose tight junction-dependent blood-brain barrier characteristics such as macromolecular impermeability and high electrical resistance. We have directly analyzed the structure and function of tight junctions in primary cultures of bovine brain endothelial cells using quantitative freeze-fracture electron microscopy, and ion and inulin permeability. The complexity of tight junctions, defined as the number of branch points per unit length of tight junctional strands, decreased 5 hours after culture but thereafter remained almost constant. In contrast, the association of tight junction particles with the cytoplasmic leaflet of the endothelial membrane bilayer (P-face) decreased continuously with a major drop between 16 hours and 24 hours. The complexity of tight junctions could be increased by elevation of intracellular cAMP levels while phorbol esters had the opposite effect. On the other hand, the P-face association of tight junction particles was enhanced by elevation of cAMP levels and by coculture of endothelial cells with astrocytes or exposure to astrocyte-conditioned medium. The latter effect on P-face association was induced by astrocytes but not fibroblasts. Elevation of cAMP levels together with astrocyte-conditioned medium synergistically increased transendothelial electrical resistance and decreased inulin permeability of primary cultures, thus confirming the effects on tight junction structure and barrier function. P-face association of tight junction particles in brain endothelial cells may therefore be a critical feature of blood-brain barrier function that can be specifically modulated by astrocytes and cAMP levels. Our results suggest an important functional role for the cytoplasmic anchorage of tight junction particles for brain endothelial barrier function in particular and probably paracellular permeability in general.

scholarly journals Decursin Inhibits VEGF-Mediated Inner Blood—Retinal Barrier Breakdown by Suppression of VEGFR-2 Activation

2009 ◽  
Vol 29 (9) ◽  
pp. 1559-1567 ◽  
Author(s):  
Jin Hyoung Kim ◽  
Jeong Hun Kim ◽  
You Mie Lee ◽  
Eun-Mi Ahn ◽  
Kyu-Won Kim ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tight Junction ◽  
Vision Loss ◽  
Retinal Vessels ◽  
Tight Junction Proteins ◽  
Blood Retinal Barrier ◽  
Retinal Endothelial Cells ◽  
Extracellular Signal ◽  
Brb Breakdown ◽  
Junction Proteins

The blood—retinal barrier (BRB) is essential for the normal structural and functional integrity of the retina, whose breakdown could cause the serious vision loss. Vascular endothelial growth factor (VEGF), as a permeable factor, induces alteration of tight junction proteins to result in BRB breakdown. Herein, we demonstrated that decursin inhibits VEGF-mediated inner BRB breakdown through suppression of VEGFR-2 signaling pathway. In retinal endothelial cells, decursin inhibited VEGF-mediated hyperpermeability. Decursin prevented VEGF-mediated loss of tight junction proteins including zonula occludens-1 (ZO-1), ZO-2, and occludin in retinal endothelial cells, which was also supported by restoration of tight junction proteins in intercellular junction. In addition, decursin significantly inhibited VEGF-mediated vascular leakage from retinal vessels, which was accompanied by prevention of loss of tight junction proteins in retinal vessels. Decursin significantly suppressed VEGF-induced VEGFR-2 phosphrylation that consequently led to inhibition of extracellular signal-regulated kinase (ERK) 1/2 activation. Moreover, decursin induced no cytotoxicity to retinal endothelial cells and no retinal toxicity under therapeutic concentrations. Therefore, our results suggest that decursin prevents VEGF-mediated BRB breakdown through blocking of loss of tight junction proteins, which might be regulated by suppression of VEGFR-2 activation. As a novel inhibitor to BRB breakdown, decursin could be applied to variable retinopathies with BRB breakdown.

scholarly journals Human pluripotent stem cell-derived brain pericyte-like cells induce blood-brain barrier properties

2018 ◽  
Author(s):  
Matthew J. Stebbins ◽  
Benjamin D. Gastfriend ◽  
Scott G. Canfield ◽  
Ming-Song Lee ◽  
Drew Richards ◽  
...  
Keyword(s):  
Stem Cells ◽  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Pluripotent Stem Cells ◽  
Neurovascular Unit ◽  
Human Pluripotent Stem Cells ◽  
Brain Barrier ◽  
Blood Brain ◽  
Brain Pericytes ◽  
The Brain

ABSTRACTBrain pericytes play an important role in the formation and maintenance of the neurovascular unit (NVU), and their dysfunction has been implicated in central nervous system (CNS) disorders. While human pluripotent stem cells (hPSCs) have been used to model other components of the NVU including brain microvascular endothelial cells (BMECs), astrocytes, and neurons, cells having brain pericyte-like phenotypes have not been described. In this study, we generated neural crest stem cells (NCSCs), the embryonic precursor to forebrain pericytes, from human pluripotent stem cells (hPSCs) and subsequently differentiated NCSCs to brain pericyte-like cells. The brain pericyte-like cells expressed marker profiles that closely resembled primary human brain pericytes, and they self-assembled with endothelial cells to support vascular tube formation. Importantly, the brain pericyte-like cells induced blood-brain barrier (BBB) properties in BMECs, including barrier enhancement and reduction of transcytosis. Finally, brain pericyte-like cells were incorporated with iPSC-derived BMECs, astrocytes, and neurons to form an isogenic human NVU model that should prove useful for the study of the BBB in CNS health, disease, and therapy.

Pathogenesis of Brain Edema and Hemorrhage: Role of the Brain Capillary

PEDIATRICS ◽  
1979 ◽  
Vol 64 (3) ◽  
pp. 357-360
Author(s):  
Gary W. Goldstein
Keyword(s):  
Endothelial Cells ◽  
Brain Edema ◽  
Tight Junctions ◽  
Interstitial Fluid ◽  
Water Soluble ◽  
Brain Capillaries ◽  
Reye's Syndrome ◽  
Anatomic Site ◽  
Brain Capillary ◽  
The Brain

It has recently been shown that the endothelial cells in brain capillaries are the anatomic site of the blood-brain barrier, and that these endothelial cells act to maintain a constant composition and volume of brain interstitial fluid.1-3 Defects in brain capillary function appear to play a role in the pathogenesis of brain edema and hemorrhage in a wide variety of diseases. Conditions as diverse as intraventricular hemorrhage of the premature, asphyxia neonatorum, lead poisoning, head injury, Reye's syndrome, osmolar coma, and the brain edema surrounding a tumor or abscess may all share the common feature of brain capillary failure. In this review, I will consider some recent advances in our understanding of the brain microvasculature that may explain their unusual susceptibility to injury. Brain capillaries have a number of important differences from capillaries in other organs. A schematic of a typical brain capillary is shown in the Figure. Unlike systemic capillaries, the endothelial cells in brain capillaries are joined together by tight junctions.3 These cellular junctions are present around the entire circumference of the capillary tube. The result is a continuous layer of endothelial cells that effectively separate the plasma from the interstitial fluid of the brain. The tight junctions are composed of a series of complex interdigitations that create a barrier so complete that water-soluble molecules and ions are unable to move into the brain between the endothelial cells. In other organs, the capillaries do not have tight junctions, and sugars, amino acids, ions, and drugs readily diffuse between endothelial cells into the interstitial fluid.

scholarly journals Pericyte-Endothelial Interactions in the Retinal Microvasculature

2020 ◽  
Vol 21 (19) ◽  
pp. 7413
Author(s):  
Hu Huang
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Neurovascular Unit ◽  
Blood Retinal Barrier ◽  
Vascular Disorders ◽  
Pathological Conditions ◽  
Retinal Microvasculature

Retinal microvasculature is crucial for the visual function of the neural retina. Pericytes and endothelial cells (ECs) are the two main cellular constituents in the retinal microvessels. Formation, maturation, and stabilization of the micro-vasculatures require pericyte-endothelial interactions, which are perturbed in many retinal vascular disorders, such as retinopathy of prematurity, retinal vein occlusion, and diabetic retinopathy. Understanding the cellular and molecular mechanisms of pericyte-endothelial interaction and perturbation can facilitate the design of therapeutic intervention for the prevention and treatment of retinal vascular disorders. Pericyte-endothelial interactions are indispensable for the integrity and functionality of retinal neurovascular unit (NVU), including vascular cells, retinal neurons, and glial cells. The essential autocrine and paracrine signaling pathways, such as Vascular endothelial growth factor (VEGF), Platelet-derived growth factor subunit B (PDGFB), Notch, Angipointein, Norrin, and Transforming growth factor-beta (TGF-β), have been well characterized for the regulation of pericyte-endothelial interactions in the neo-vessel formation processes (vasculogenesis and angiogenesis) during embryonic development. They also play a vital role in stabilizing and remodeling mature vasculature under pathological conditions. Awry signals, aberrant metabolisms, and pathological conditions, such as oxidative stress and inflammation, can disrupt the communication between pericytes and endothelial cells, thereby resulting in the breakdown of the blood-retinal barrier (BRB) and other microangiopathies. The emerging evidence supports extracellular exosomes’ roles in the (mis)communications between the two cell types. This review summarizes the essential knowledge and updates about new advancements in pericyte-EC interaction and communication, emphasizing the retinal microvasculature.

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

2015 ◽  
pp. S259-S264 ◽  
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 ◽  
The Brain

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.

scholarly journals The “Frail” Brain Blood Barrier in Neurodegenerative Diseases: Role of Early Disruption of Endothelial Cell-to-Cell Connections

2018 ◽  
Vol 19 (9) ◽  
pp. 2693 ◽  
Author(s):  
Jessica Maiuolo ◽  
Micaela Gliozzi ◽  
Vincenzo Musolino ◽  
Miriam Scicchitano ◽  
Cristina Carresi ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Molecular Mechanisms ◽  
Neurovascular Unit ◽  
Cellular Component ◽  
Demarcation Line ◽  
Novel Therapeutic Strategies ◽  
The Brain ◽  
Brain Homeostasis ◽  
Junction Proteins

The main neurovascular unit of the Blood Brain Barrier (BBB) consists of a cellular component, which includes endothelial cells, astrocytes, pericytes, microglia, neurons, and oligodendrocytes as well as a non-cellular component resulting from the extracellular matrix. The endothelial cells are the major vital components of the BBB able to preserve the brain homeostasis. These cells are situated along the demarcation line between the bloodstream and the brain. Therefore, an alteration or the progressive disruption of the endothelial layer may clearly impair the brain homeostasis. The proper functioning of the brain endothelial cells is generally ensured by two elements: (1) the presence of junction proteins and (2) the preservation of a specific polarity involving an apical-luminal and a basolateral-abluminal membrane. This review intends to identify the molecular mechanisms underlying BBB function and their changes occurring in early stages of neurodegenerative processes in order to develop novel therapeutic strategies aimed to counteract neurodegenerative disorders.

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