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Age-associated changes in murine endothelial gene expression and chromatin accessibility correlate with impaired blood-brain barrier integrity and elevated risk of intracerebral hemorrhage

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE218649 | GEO | 2023/09/20

REPOSITORIES: GEO

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Age-associated changes in murine endothelial gene expression correlate with impaired blood-brain barrier integrity and elevated risk of intracerebral hemorrhage.

Project description:We studied changes in gene expression in Endothelial Cells isolated from murine brains of increasing ages of 2, 6, 12, 18, and 24 months. We then performed linear regression analysis to compare the changes in gene expression in the endothelial cells with age.

2023-09-20 | GSE216004 | GEO

Age-associated changes in murine endothelial gene expression and chromatin accessibility correlate with impaired blood-brain barrier integrity and elevated risk of intracerebral hemorrhage [RRBS]

Project description:Intracerebral hemorrhage (ICH), a devastating form of stroke, is a leading global cause of human death and disability. The major risk factors for ICH include increasing age, hypertension and cerebral amyloid angiopathy. Despite high mortality and morbidity associated with ICH, the mechanisms leading to blood-brain barrier (BBB) dysfunction with age and development of hemorrhagic stroke is poorly understood. In the vasculature of the central nervous system, endothelial cells (ECs) constitute the core component of the BBB and provide a physical barrier due to tight junctions, adherens junctions, and basement membrane layers. In this study, we show in brains of mice that incidents of intracerebral bleeding increase with advancing age. After isolation of an enriched population of cerebral ECs, we studied gene expression in ECs isolated from murine brains of increasing ages of 2, 6, 12, 18, and 24 months. The study reveals age-dependent dysregulation of 1388 genes in the ECs, including many involved in the maintenance of BBB and vascular integrity. Since epigenetic mechanisms regulate gene expression, we also investigated age-dependent changes at the levels of CpG methylation and accessible chromatin in cerebral ECs. Our study reveals correlations between age-dependent changes in chromatin structure and gene expression. We find significant age-dependent downregulation of the apelin receptor (Aplnr) gene along with an age-dependent reduction in chromatin accessibility of the promoter of this gene. Aplnr is known to play a crucial role in positive regulation of vasodilation and is implicated in vascular health. Interestingly, we also observe an age-dependent reduction in the protein expression levels of the apelin receptor in the brain, potentially implicating the apelin receptor to be critical for the increased risk of intracerebral hemorrhage with ageing.

2023-09-20 | GSE218648 | GEO

Age-associated changes in murine endothelial gene expression and chromatin accessibility correlate with impaired blood-brain barrier integrity and elevated risk of intracerebral hemorrhage [ATAC-seq]

2023-09-20 | GSE218647 | GEO

Age-associated changes in murine endothelial gene expression correlate with impaired blood-brain barrier integrity and elevated risk of intracerebral hemorrhage.

Project description:Age-associated changes in murine endothelial gene expression correlate with impaired blood-brain barrier integrity and elevated risk of intracerebral hemorrhage.

| PRJNA891694 | ENA

Age-associated changes in murine endothelial gene expression and chromatin accessibility correlate with impaired blood-brain barrier integrity and elevated risk of intracerebral hemorrhage

Project description:Age-associated changes in murine endothelial gene expression and chromatin accessibility correlate with impaired blood-brain barrier integrity and elevated risk of intracerebral hemorrhage

| PRJNA904753 | ENA

Age-associated changes in murine endothelial gene expression and chromatin accessibility correlate with impaired blood-brain barrier integrity and elevated risk of intracerebral hemorrhage [RRBS]

| PRJNA904757 | ENA

Age-associated changes in murine endothelial gene expression and chromatin accessibility correlate with impaired blood-brain barrier integrity and elevated risk of intracerebral hemorrhage [ATAC-seq]

| PRJNA904754 | ENA

Valproate Sodium Protects Blood Brain Barrier Integrity in Intracerebral Hemorrhage Mice.

Project description:Valproate sodium (VPA) is a traditional antiepileptic drug with a neuroprotective role in cerebrovascular disease. After intracerebral hemorrhage (ICH), mechanical compression by hematoma, neuroinflammation, oxidative stress, and cytotoxicity of hematoma lysates caused the destruction of the blood brain barrier (BBB). Targeting BBB is a major therapeutic method for patients with ICH. The purpose of the present study was to explore the role of VPA in preserving BBB integrity in the ICH model and investigate the underlying molecular mechanisms. One hundred and thirty-six adult male CD1 mice were randomly divided into five groups in the study. Mice subjected to ICH were administered intraperitoneally with VPA at 3, 24, and 48 h post-ICH, respectively. Neurobehavioral assessments, BBB permeability, Evans blue fluorescence, hematoma volume, and protein expression were evaluated. The administration of VPA reduced BBB permeability and improved the neurobehavior significantly post-ICH. VPA administration significantly decreased the expression of phosphorylated nuclear factor-kappa B (p-NFκB), matrix metalloproteinases 9 (MMP9), tumor necrosis factorα (TNFα), and interleukin-6 (IL-6), while it enhanced the expression of claudin 5 and occludin in the brain. In conclusion, VPA administration maintained the integrity of BBB after experimental ICH, thus reducing brain edema and improving the neurological outcomes. Therefore, VPA administration might be a new therapeutic method to protect BBB integrity for patients with ICH.

| S-EPMC7676278 | biostudies-literature

Genetically Elevated LDL Associates with Lower Risk of Intracerebral Hemorrhage.

Project description:ObjectiveObservational studies point to an inverse correlation between low-density lipoprotein (LDL) cholesterol levels and risk of intracerebral hemorrhage (ICH), but it remains unclear whether this association is causal. We tested the hypothesis that genetically elevated LDL is associated with reduced risk of ICH.MethodsWe constructed one polygenic risk score (PRS) per lipid trait (total cholesterol, LDL, high-density lipoprotein [HDL], and triglycerides) using independent genomewide significant single nucleotide polymorphisms (SNPs) for each trait. We used data from 316,428 individuals enrolled in the UK Biobank to estimate the effect of each PRS on its corresponding trait, and data from 1,286 ICH cases and 1,261 matched controls to estimate the effect of each PRS on ICH risk. We used these estimates to conduct Mendelian Randomization (MR) analyses.ResultsWe identified 410, 339, 393, and 317 lipid-related SNPs for total cholesterol, LDL, HDL, and triglycerides, respectively. All four PRSs were strongly associated with their corresponding trait (all p < 1.00 × 10-100 ). While one SD increase in the PRSs for total cholesterol (odds ratio [OR] = 0.92; 95% confidence interval [CI] = 0.85-0.99; p = 0.03) and LDL cholesterol (OR = 0.88; 95% CI = 0.81-0.95; p = 0.002) were inversely associated with ICH risk, no significant associations were found for HDL and triglycerides (both p > 0.05). MR analyses indicated that 1mmol/L (38.67mg/dL) increase of genetically instrumented total and LDL cholesterol were associated with 23% (OR = 0.77; 95% CI = 0.65-0.98; p = 0.03) and 41% lower risks of ICH (OR = 0.59; 95% CI = 0.42-0.82; p = 0.002), respectively.InterpretationGenetically elevated LDL levels were associated with lower risk of ICH, providing support for a potential causal role of LDL cholesterol in ICH. ANN NEUROL 2020 ANN NEUROL 2020;88:56-66.

| S-EPMC7523882 | biostudies-literature

Upregulation of AQP4 Improves Blood-Brain Barrier Integrity and Perihematomal Edema Following Intracerebral Hemorrhage.

Project description:In intracerebral hemorrhage (ICH), delayed secondary neural damages largely occur from perihematomal edema (PHE) resulting from the disruption of the blood-brain barrier (BBB). PHE is often considered the principal cause of morbidity and mortality in patients with ICH. Nevertheless, the main cellular mechanism as well as the specific BBB component involved in the formation of PHE after ICH remains elusive. Herein, we evaluated the role of AQP4, a water channel expressed on the astrocytes of the BBB, in the formation of PHE in ICH. The static and dynamic functions of the BBB were evaluated by analyzing the microstructure and leakage assay. Protein changes in the PHE lesion were analyzed and the control mechanism of AQP4 expression by reactive oxygen species was also investigated. Delayed PHE formation due to BBB disruption after ICH was confirmed by the decreased coverage of multiple BBB components and increased dynamic leakages. Microstructure assay showed that among the BBB components, AQP4 showed a markedly decreased expression in the PHE lesions. The decrease in AQP4 was due to microenvironmental ROS derived from the hemorrhage and was restored by treatment with ROS scavenger. AQP4-deficient mice had significantly larger PHE lesions and unfavorable survival outcomes compared with wild-type mice. Our data identify AQP4 as a specific BBB-modulating target for alleviating PHE in ICH. Further comprehensive studies are needed to form the preclinical basis for the use of AQP4 enhancers as BBB modulators for preventing delayed cerebral edema after ICH.

| S-EPMC8804112 | biostudies-literature

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