Ischemia Reperfusion Injury Induced Blood Brain Barrier Dysfunction and the Involved Molecular Mechanism

Guo, Xi; Liu, Ru; Meng, Jia; Wang, Qun; Wu, Jianping

doi:10.1007/s11064-023-03923-x

Cited by 19 publications

(9 citation statements)

References 156 publications

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“…5 A, B) and M1-type macrophage markers ( Cd86 , Fig. 5 A, B) compared with Lrg1 −/− mice after MCAO/R [ 34 , 35 ]. In contrast, microglial cells and macrophages in the MCAO/R + Lrg1 −/− group had higher expression levels of anti-inflammatory molecules ( Il10 , Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Cerebral ischemia‒reperfusion injury is an extremely complex process that involves disruption of the blood‒brain barrier (BBB), brain inflammation, and increased neuronal apoptosis, which are associated with various cellular components in the brain. BBB breakdown after cerebral ischemia‒reperfusion injury is mainly manifested by a decrease in the connectivity between the cell components of the BBB (including pericytes, endothelial cells, astrocytes, and basement membrane) and an increase in leakage [ 4 , 5 ]. The progression of cerebral ischemia‒reperfusion injury is also associated with various immune cells, which play a dual role in the progression of cerebral ischemia‒reperfusion injury.…”

Section: Introductionmentioning

confidence: 99%

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Single-cell RNA sequencing unveils Lrg1's role in cerebral ischemia‒reperfusion injury by modulating various cells

Ruan,

Cao,

Qian

et al. 2023

J Neuroinflammation

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Background and purpose Cerebral ischemia‒reperfusion injury causes significant harm to human health and is a major contributor to stroke-related deaths worldwide. Current treatments are limited, and new, more effective prevention and treatment strategies that target multiple cell components are urgently needed. Leucine-rich alpha-2 glycoprotein 1 (Lrg1) appears to be associated with the progression of cerebral ischemia‒reperfusion injury, but the exact mechanism of it is unknown. Methods Wild-type (WT) and Lrg1 knockout (Lrg1−/−) mice were used to investigate the role of Lrg1 after cerebral ischemia‒reperfusion injury. The effects of Lrg1 knockout on brain infarct volume, blood‒brain barrier permeability, and neurological score (based on 2,3,5-triphenyl tetrazolium chloride, evans blue dye, hematoxylin, and eosin staining) were assessed. Single-cell RNA sequencing (scRNA-seq), immunofluorescence, and microvascular albumin leakage tests were utilized to investigate alterations in various cell components in brain tissue after Lrg1 knockout. Results Lrg1 expression was increased in various cell types of brain tissue after cerebral ischemia‒reperfusion injury. Lrg1 knockout reduced cerebral edema and infarct size and improved neurological function after cerebral ischemia‒reperfusion injury. Single-cell RNA sequencing analysis of WT and Lrg1−/− mouse brain tissues after cerebral ischemia‒reperfusion injury revealed that Lrg1 knockout enhances blood‒brain barrier (BBB) by upregulating claudin 11, integrin β5, protocadherin 9, and annexin A2. Lrg1 knockout also promoted an anti-inflammatory and tissue-repairing phenotype in microglia and macrophages while reducing neuron and oligodendrocyte cell death. Conclusions Our results has shown that Lrg1 mediates numerous pathological processes involved in cerebral ischemia‒reperfusion injury by altering the functional states of various cell types, thereby rendering it a promising therapeutic target for cerebral ischemia‒reperfusion injury.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Single-cell RNA sequencing unveils Lrg1's role in cerebral ischemia‒reperfusion injury by modulating various cells

Ruan,

Cao,

Qian

et al. 2023

J Neuroinflammation

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“…Future studies will have to assess whether AITC administration is also able to increase NO production in the human brain. Interestingly, the production of high levels of ROS plays a crucial role in cerebral ischemia-reperfusion injury by causing endothelial dysfunction and BBB disruption [ 66 , 67 , 68 ]. However, it has long been known that low ROS signalling regulates multiple endothelial functions and could be instrumental in rescuing endothelial dysfunction in cerebrovascular and neurological disorders [ 58 , 69 , 70 ], including atherosclerosis, acute myocardial infarction, stroke and traumatic brain injury.…”

Section: Discussionmentioning

confidence: 99%

Allyl Isothiocianate Induces Ca2+ Signals and Nitric Oxide Release by Inducing Reactive Oxygen Species Production in the Human Cerebrovascular Endothelial Cell Line hCMEC/D3

Berra‐Romani

Brunetti

Pellavio

et al. 2023

Cells

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Nitric oxide (NO) represents a crucial mediator to regulate cerebral blood flow (CBF) in the human brain both under basal conditions and in response to somatosensory stimulation. An increase in intracellular Ca2+ concentrations ([Ca2+]i) stimulates the endothelial NO synthase to produce NO in human cerebrovascular endothelial cells. Therefore, targeting the endothelial ion channel machinery could represent a promising strategy to rescue endothelial NO signalling in traumatic brain injury and neurodegenerative disorders. Allyl isothiocyanate (AITC), a major active constituent of cruciferous vegetables, was found to increase CBF in non-human preclinical models, but it is still unknown whether it stimulates NO release in human brain capillary endothelial cells. In the present investigation, we showed that AITC evoked a Ca2+-dependent NO release in the human cerebrovascular endothelial cell line, hCMEC/D3. The Ca2+ response to AITC was shaped by both intra- and extracellular Ca2+ sources, although it was insensitive to the pharmacological blockade of transient receptor potential ankyrin 1, which is regarded to be among the main molecular targets of AITC. In accord, AITC failed to induce transmembrane currents or to elicit membrane hyperpolarization, although NS309, a selective opener of the small- and intermediate-conductance Ca2+-activated K+ channels, induced a significant membrane hyperpolarization. The AITC-evoked Ca2+ signal was triggered by the production of cytosolic, but not mitochondrial, reactive oxygen species (ROS), and was supported by store-operated Ca2+ entry (SOCE). Conversely, the Ca2+ response to AITC did not require Ca2+ mobilization from the endoplasmic reticulum, lysosomes or mitochondria. However, pharmacological manipulation revealed that AITC-dependent ROS generation inhibited plasma membrane Ca2+-ATPase (PMCA) activity, thereby attenuating Ca2+ removal across the plasma membrane and resulting in a sustained increase in [Ca2+]i. In accord, the AITC-evoked NO release was driven by ROS generation and required ROS-dependent inhibition of PMCA activity. These data suggest that AITC could be exploited to restore NO signalling and restore CBF in brain disorders that feature neurovascular dysfunction.

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“…5A and B) and M1-type macrophage markers (Cd86, Fig. 5A and B) compared with Lrg1 -/mice after MCAO/R 34,35 . In contrast, microglial cells and macrophages in the MCAO/R + Lrg1 -/group had higher expression levels of anti-in ammatory molecules (Il10, Fig.…”

Section: Conventional Knockout Of Lrg1 Restricts the Bbb Dysfunction ...mentioning

confidence: 93%

Single-Cell RNA Sequencing Unveils Lrg1's Role in Cerebral Ischemia‒Reperfusion Injury by Modulating Various Cells

Ruan

Cao

Qian

et al. 2023

Preprint

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Background and purpose: Cerebral ischemia‒reperfusion injury causes significant harm to human health and is a major contributor to stroke-related deaths worldwide. Current treatments are limited, and new, more effective prevention and treatment strategies that target multiple cell components are urgently needed. Leucine-rich alpha-2 glycoprotein 1 (Lrg1) appears to be associated with the progression of cerebral ischemia‒reperfusion injury, but the exact mechanism of it is unknown. Methods: Wild-type (WT) and Lrg1 knockout (Lrg1-/-) mice were used to investigate the role of Lrg1 after cerebral ischemia‒reperfusion injury. The effects of Lrg1 knockout on brain infarct volume, blood‒brain barrier permeability, and neurological score (based on 2,3,5-triphenyl tetrazolium chloride, evans blue dye, hematoxylin, and eosin staining) were assessed. Single-cell RNA sequencing (scRNA-seq), immunofluorescence, and microvascular albumin leakage tests were utilized to investigate alterations in various cell components in brain tissue after Lrg1 knockout. Results: Lrg1 expression was increased in various cell types of brain tissue after cerebral ischemia‒reperfusion injury. Lrg1 knockout reduced cerebral edema and infarct size and improved neurological function after cerebral ischemia‒reperfusion injury. Single-cell RNA sequencing analysis of WT and Lrg1-/- mouse brain tissues after cerebral ischemia‒reperfusion injury revealed that Lrg1 knockout enhances blood‒brain barrier (BBB) permeability by upregulating claudin 11, integrin β5, protocadherin 9, and annexin A2. Lrg1 knockout also promoted an anti-inflammatory and tissue-repairing phenotype in microglia and macrophages while reducing neuron and oligodendrocyte cell death. Conclusions: Convincing evidence has shown that Lrg1 mediates numerous pathological processes involved in cerebral ischemia‒reperfusion injury by altering the functional states of various cell types, thereby rendering it a promising therapeutic target for cerebral ischemia‒reperfusion injury.

show abstract

Ischemia Reperfusion Injury Induced Blood Brain Barrier Dysfunction and the Involved Molecular Mechanism

Cited by 19 publications

References 156 publications

Single-cell RNA sequencing unveils Lrg1's role in cerebral ischemia‒reperfusion injury by modulating various cells

Single-cell RNA sequencing unveils Lrg1's role in cerebral ischemia‒reperfusion injury by modulating various cells

Allyl Isothiocianate Induces Ca2+ Signals and Nitric Oxide Release by Inducing Reactive Oxygen Species Production in the Human Cerebrovascular Endothelial Cell Line hCMEC/D3

Single-Cell RNA Sequencing Unveils Lrg1's Role in Cerebral Ischemia‒Reperfusion Injury by Modulating Various Cells

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