scholarly journals Endothelium-targeted deletion of the miR-15a/16-1 cluster ameliorates blood-brain barrier dysfunction in ischemic stroke

2020 ◽  
Vol 13 (626) ◽  
pp. eaay5686 ◽  
Author(s):  
Feifei Ma ◽  
Ping Sun ◽  
Xuejing Zhang ◽  
Milton H. Hamblin ◽  
Ke-Jie Yin
Keyword(s):  
Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Molecular Mechanisms ◽  
Neuronal Loss ◽  
Glucose Deprivation ◽  
Brain Barrier ◽  
Protein Abundance ◽  
Barrier Dysfunction ◽  
Small Noncoding Rnas ◽  
Blood Brain

The blood-brain barrier (BBB) maintains a stable brain microenvironment. Breakdown of BBB integrity during cerebral ischemia initiates a devastating cascade of events that eventually leads to neuronal loss. MicroRNAs are small noncoding RNAs that suppress protein expression, and we previously showed that the miR-15a/16-1 cluster is involved in the pathogenesis of ischemic brain injury. Here, we demonstrated that when subjected to experimentally induced stroke, mice with an endothelial cell (EC)–selective deletion of miR-15a/16-1 had smaller brain infarcts, reduced BBB leakage, and decreased infiltration of peripheral immune cells. These mice also showed reduced infiltration of proinflammatory M1-type microglia/macrophage in the peri-infarct area without changes in the number of resolving M2-type cells. Stroke decreases claudin-5 abundance, and we found that EC-selective miR-15a/16-1 deletion enhanced claudin-5 mRNA and protein abundance in ischemic mouse brains. In cultured mouse brain microvascular ECs (mBMECs), the miR-15a/16-1 cluster directly bound to the 3′ untranslated region (3′UTR) of Claudin-5, and lentivirus-mediated ablation of miR-15a/16-1 diminished oxygen-glucose deprivation (OGD)–induced down-regulation of claudin-5 mRNA and protein abundance and endothelial barrier dysfunction. These findings suggest that genetic deletion of endothelial miR-15a/16-1 suppresses BBB pathologies after ischemic stroke. Elucidating the molecular mechanisms of miR-15a/16-1–mediated BBB dysfunction may enable the discovery of new therapies for ischemic stroke.

scholarly journals Mechanisms of Blood–Brain Barrier Dysfunction in Traumatic Brain Injury

2020 ◽  
Vol 21 (9) ◽  
pp. 3344 ◽  
Author(s):  
Alison Cash ◽  
Michelle H. Theus
Keyword(s):  
Blood Brain Barrier ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Brain Injuries ◽  
The United States ◽  
Brain Barrier ◽  
Detection Methods ◽  
Secondary Injury ◽  
Barrier Dysfunction ◽  
Blood Brain

Traumatic brain injuries (TBIs) account for the majority of injury-related deaths in the United States with roughly two million TBIs occurring annually. Due to the spectrum of severity and heterogeneity in TBIs, investigation into the secondary injury is necessary in order to formulate an effective treatment. A mechanical consequence of trauma involves dysregulation of the blood–brain barrier (BBB) which contributes to secondary injury and exposure of peripheral components to the brain parenchyma. Recent studies have shed light on the mechanisms of BBB breakdown in TBI including novel intracellular signaling and cell–cell interactions within the BBB niche. The current review provides an overview of the BBB, novel detection methods for disruption, and the cellular and molecular mechanisms implicated in regulating its stability following TBI.

Exacerbation of oxygen–glucose deprivation-induced blood–brain barrier disruption: potential pathogenic role of interleukin-9 in ischemic stroke

2017 ◽  
Vol 131 (13) ◽  
pp. 1499-1513 ◽  
Author(s):  
Sha Tan ◽  
Yilong Shan ◽  
Yuge Wang ◽  
Yinyao Lin ◽  
Siyuan Liao ◽  
...  
Keyword(s):  
T Cells ◽  
Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Mononuclear Cells ◽  
Biological Effects ◽  
Glucose Deprivation ◽  
Brain Barrier ◽  
Oxygen Glucose Deprivation ◽  
Expression Levels ◽  
Blood Brain

Interleukin (IL)-9 exerts a variety of functions in autoimmune diseases. However, its role in ischemic brain injury remains unknown. The present study explored the biological effects of IL-9 in ischemic stroke (IS). We recruited 42 patients newly diagnosed with IS and 22 age- and sex-matched healthy controls. The expression levels of IL-9 and percentages of IL-9-producing T cells, including CD3+CD4+IL-9+ and CD3+CD8+IL-9+ cells, were determined in peripheral blood mononuclear cells (PBMCs) obtained from patients and control individuals. We also investigated the effects of IL-9 on the blood–brain barrier (BBB) following oxygen–glucose deprivation (OGD) and the potential downstream signaling pathways. We found that patients with IS had higher IL-9 expression levels and increased percentages of IL-9-producing T cells in their PBMCs. The percentages of CD3+CD4+IL-9+ and CD3+CD8+IL-9+ T cells were positively correlated with the severity of illness. In in vitro experiments using bEnd.3 cells, exogenously administered IL-9 exacerbated the loss of tight junction proteins (TJPs) in cells subjected to OGD plus reoxygenation (RO). This effect was mediated via activation of IL-9 receptors, which increased the level of endothelial nitric oxide synthase (eNOS), as well as through up-regulated phosphorylation of signal transducer and activator of transcription 1 and 3 and down-regulated phosphorylated protein kinase B/phosphorylated phosphatidylinositol 3-kinase signaling. These results indicate that IL-9 has a destructive effect on the BBB following OGD, at least in part by inducing eNOS production, and raise the possibility of targetting IL-9 for therapeutic intervention in IS.

scholarly journals Blood-brain barrier dysfunction and recovery after ischemic stroke

2018 ◽  
Vol 163-164 ◽  
pp. 144-171 ◽  
Author(s):  
Xiaoyan Jiang ◽  
Anuska V. Andjelkovic ◽  
Ling Zhu ◽  
Tuo Yang ◽  
Michael V.L. Bennett ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Barrier Dysfunction ◽  
Blood Brain

Attenuated Blood-Brain Barrier Dysfunction by XQ-1H Following Ischemic Stroke in Hyperlipidemic Rats

2014 ◽  
Vol 52 (1) ◽  
pp. 162-175 ◽  
Author(s):  
Weirong Fang ◽  
Lan Sha ◽  
Nandani Darshika Kodithuwakku ◽  
Jie Wei ◽  
Rui Zhang ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Barrier Dysfunction ◽  
Blood Brain

scholarly journals Caveolae-Mediated Endothelial Transcytosis across the Blood-Brain Barrier in Acute Ischemic Stroke

2021 ◽  
Vol 10 (17) ◽  
pp. 3795
Author(s):  
Min Zhou ◽  
Samuel X. Shi ◽  
Ning Liu ◽  
Yinghua Jiang ◽  
Mardeen S. Karim ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Molecular Mechanisms ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Hemorrhagic Transformation ◽  
Brain Barrier ◽  
Blood Brain ◽  
Entry Points

Blood-brain barrier (BBB) disruption following ischemic stroke (IS) contributes to hemorrhagic transformation, brain edema, increased neural dysfunction, secondary injury, and mortality. Brain endothelial cells form a para and transcellular barrier to most blood-borne solutes via tight junctions (TJs) and rare transcytotic vesicles. The prevailing view attributes the destruction of TJs to the resulting BBB damage following IS. Recent studies define a stepwise impairment of the transcellular barrier followed by the paracellular barrier which accounts for the BBB leakage in IS. The increased endothelial transcytosis that has been proven to be caveolae-mediated, precedes and is independent of TJs disintegration. Thus, our understanding of post stroke BBB deficits needs to be revised. These recent findings could provide a conceptual basis for the development of alternative treatment strategies. Presently, our concept of how BBB endothelial transcytosis develops is incomplete, and treatment options remain limited. This review summarizes the cellular structure and biological classification of endothelial transcytosis at the BBB and reviews related molecular mechanisms. Meanwhile, relevant transcytosis-targeted therapeutic strategies for IS and research entry points are prospected.

scholarly journals Nicotinamide Mononucleotide Adenylyltransferase 1 Regulates Cerebral Ischemia-Induced Blood–Brain Barrier Disruption Through NAD+/SIRT1 Signaling Pathway

2021 ◽  
Author(s):  
Yang Zhang ◽  
Xun Guo ◽  
Zhifeng Peng ◽  
Chang Liu ◽  
Lili Ren ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Signaling Pathway ◽  
Blood Brain Barrier ◽  
Molecular Mechanisms ◽  
Sirtuin 1 ◽  
Brain Barrier ◽  
Blood Brain ◽  
Nicotinamide Mononucleotide ◽  
Nicotinamide Mononucleotide Adenylyltransferase ◽  
Bbb Permeability

Abstract The molecular mechanisms of blood–brain barrier (BBB) disruption in the early stage after ischemic stroke are poorly understood. In the present study, we investigated the potential role of nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1) in ischemia-induced BBB damage using an animal middle cerebral artery occlusion (MCAO) model of ischemic stroke. Recombinant human NMNAT1 (rh-NMNAT1) was administered intranasally and Sirtuin 1 (SIRT1) siRNA was administered by intracerebroventricular injection. Our results indicated that rh-NMNAT1 reduced infarct volume, improved functional outcome and decreased BBB permeability in mice after ischemic stroke. Furthermore, rh-NMNAT1 prevented the loss of tight junction proteins (occludin and claudin-5) and reduced cell apoptosis in ischemic microvessels. NMNAT1-mediated BBB permeability was correlated with the elevation of nicotinamide adenine dinucleotide (NAD+)/NADH and SIRT1 level in ischemic microvessels. In addition, rh-NMNAT1 treatment significantly decreased the levels of acetylated nuclear factor-κB, acetylated p53 and matrix metalloproteinase-9 in ischemic microvessels. Moreover, the protective effects of rh-NMNAT1 were reversed by SIRT1 siRNA. In conclusion, these findings indicate that NMNAT1 protects BBB after ischemic stroke in mice which was in part via the NAD+/SIRT1 signaling pathway in brain microvascular endothelial cells. NMNAT1 may be a novel potential therapeutic target for reducing BBB disruption after ischemic stroke.

Ιmmunity, Vascular Aging, and Stroke

2022 ◽  
Vol 29 ◽  
Author(s):  
Anna-Maria Louka ◽  
Dimitrios Sagris ◽  
George Ntaios
Keyword(s):  
Blood Brain Barrier ◽  
Molecular Mechanisms ◽  
Vascular Dysfunction ◽  
Vascular Inflammation ◽  
Brain Barrier ◽  
Low Grade ◽  
Vascular Aging ◽  
Barrier Dysfunction ◽  
Blood Brain

Abstract: Stroke is one of the most devastating manifestations of cardiovascular disease. Growing age, arterial hypertension, and atherosclerosis are identified as independent risk factors for stroke, primarily due to structural and functional alterations in the cerebrovascular tree. Recent data from in vitro and clinical studies have suggested that the immune system influences atherosclerosis, promoting vascular stiffness and vascular aging and contributing to ischemic stroke, intracranial haemorrhage and microbleeds, white matter disease, and cognitive decline. Furthermore, aging is related to a chronic low-grade inflammatory state, in which macrophage, neutrophils, natural killer (NK cells), and B and T lymphocytes act as major effectors of the immune-mediated cell responses. Moreover, oxidative stress and vascular inflammation are correlated with endothelial dysfunction, vascular aging, blood-brain barrier disruption, lacunar lesions, and neurodegenerative disorders. This review discusses the pathophysiological roles of fundamental cellular and molecular mechanisms of aging, including the complex interplay between them and innate immunity, as well as vascular dysfunction, arterial stiffness, atherosclerosis, atherothrombosis, systemic inflammation, and blood-brain barrier dysfunction.

scholarly journals Interleukin-1β-induced barrier dysfunction is signaled through PKC-θ in human brain microvascular endothelium

2012 ◽  
Vol 302 (10) ◽  
pp. C1513-C1522 ◽  
Author(s):  
Robert R. Rigor ◽  
Richard S. Beard ◽  
Olesya P. Litovka ◽  
Sarah Y. Yuan
Keyword(s):  
Human Brain ◽  
Blood Brain Barrier ◽  
Molecular Mechanisms ◽  
Brain Barrier ◽  
Brain Diseases ◽  
Barrier Dysfunction ◽  
Microvascular Endothelium ◽  
Blood Brain ◽  
Pkc Isoforms ◽  
Junction Protein

Blood-brain barrier dysfunction is a serious consequence of inflammatory brain diseases, cerebral infections, and trauma. The proinflammatory cytokine interleukin (IL)-1β is central to neuroinflammation and contributes to brain microvascular leakage and edema formation. Although it is well known that IL-1β exposure directly induces hyperpermeability in brain microvascular endothelium, the molecular mechanisms mediating this response are not completely understood. In the present study, we found that exposure of the human brain microvascular endothelium to IL-1β triggered activation of novel PKC isoforms δ, μ, and θ, followed by decreased transendothelial electrical resistance (TER). The IL-1β-induced decrease in TER was prevented by small hairpin RNA silencing of PKC-θ or by treatment with the isoform-selective PKC inhibitor Gö6976 but not by PKC inhibitors that are selective for all PKC isoforms other than PKC-θ. Decreased TER coincided with increased phosphorylation of regulatory myosin light chain and with increased proapoptotic signaling indicated by decreased uptake of mitotracker red in response to IL-1β treatment. However, neither of these observed effects were prevented by Gö6976 treatment, indicating lack of causality with respect to decreased TER. Instead, our data indicated that the mechanism of decreased TER involves PKC-θ-dependent phosphorylation of the tight junction protein zona occludens (ZO)-1. Because IL-1β is a central inflammatory mediator, our interpretation is that inhibition of PKC-θ or inhibition of ZO-1 phosphorylation could be viable strategies for preventing blood-brain barrier dysfunction under a variety of neuroinflammatory conditions.

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