Transcriptional profiling identifies white matter changes in eNOS+/- mice II
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE207960 | GEO | 2022/07/12
REPOSITORIES: GEO
Similar Datasets
Project description:To elucidate the effects of eNOS deficiency at the transcriptional level, we performed RNA-seq on white matter and grey matter regions dissected from the brains of eNOS+/+ and eNOS+/- mice
2022-07-12 | GSE207961 | GEO
Project description:Vascular cognitive impairment and dementia (VCID) is the second most common form of dementia after Alzheimer’s disease (AD). Currently, the mechanistic insights into the evolution and progression of VCID remain elusive. White matter change represents an invariant feature. Compelling clinical neuroimaging and pathological evidence suggest a link between white matter changes and neurodegeneration. Our prior study detected hypoperfused lesions in mice with partial deficiency of endothelial nitric oxide (eNOS) at very young age, precisely matching to those hypoperfused areas identified in preclinical AD patients. White matter tracts are particularly susceptible to the vascular damage induced by chronic hypoperfusion. Using immunohistochemistry, we detected severe demyelination in the middle aged eNOS-deficient mice. The demyelinated areas were confined to cortical and subcortical areas including the corpus callosum and hippocampus. The intensity of demyelination correlated with behavioral deficits of gait and associative recognition memory performances. By Evans blue angiography, we detected blood-brain barrier (BBB) leakage as another early pathological change affecting frontal and parietal cortex in eNOS-deficient mic. Sodium nitrate fortified drinking water provided to young and middle aged eNOS-deficient mice completely prevented non-perfusion, BBB leakage, and white matter pathology, indicating that impaired endothelium-derived NO signaling may have caused these pathological events. Furthermore, genome-wide transcriptomic analysis revealed altered gene clusters most related to mitochondrial respiratory pathways selectively in the white matter of young eNOS-deficient mice. Using eNOS-deficient mice, we identified BBB breakdown and hypoperfusion as the two earliest pathological events, resulting from insufficient vascular NO signaling. We speculate that the compromised BBB and mild chronic hypoperfusion trigger vascular damage, along with oxidative stress and astrogliosis, accounting for the white matter pathological changes in the eNOS-deficient mouse model. We conclude that eNOS-deficient mice represent an ideal spontaneous evolving model for studying the earliest events leading to spontaneous white matter changes, which will be instrumental to future therapeutic testing of drug candidates and for targeting novel/specific vascular mechanisms contributing to VCID and AD.
2022-07-12 | GSE207693 | GEO
Project description:Transcriptional profiling identifies white matter changes in eNOS+/- mice
| PRJNA857742 | ENA
Project description:Transcriptional profiling identifies white matter changes in eNOS+/- mice I
| PRJNA857743 | ENA
Project description:Transcriptional profiling identifies white matter changes in eNOS+/- mice II
| PRJNA857744 | ENA
Project description:Endothelial nitric oxide synthase (eNOS) catalyzes the conversion of L-arginine and molecular oxygen into L-citrulline and nitric oxide (NO), a gaseous second messenger that influences cardiovascular physiology and disease. Several mechanisms regulate eNOS activity and function, including phosphorylation at Ser and Thr residues and protein-protein interactions. Combining a tandem affinity purification approach and mass spectrometry, we identified stromal cell-derived factor 2 (SDF2) as a component of the eNOS macromolecular complex in endothelial cells. SDF2 knockdown impaired agonist stimulated NO synthesis and decreased phosphorylation of eNOS at Ser1177, a key event required for maximal activation of eNOS. Conversely, SDF2 overexpression dose-dependently increased NO synthesis through a mechanism involving Akt and calcium (induced with ionomycin), which increased the phosphorylation of Ser1177 in eNOS. NO synthesis by iNOS (inducible NOS) and nNOS (neuronal NOS) was also enhanced upon SDF2 overexpression. We found that SDF2 was a client protein of the chaperone protein Hsp90, interacting preferentially with the M domain of Hsp90, which is the same domain that binds to eNOS. In endothelial cells exposed to vascular endothelial growth factor (VEGF), SDF2 was required for the binding of Hsp90 and calmodulin to eNOS, resulting in eNOS phosphorylation and activation. Thus, our data describe a function for SDF2 as a component of the Hsp90-eNOS complex that is critical for signal transduction in endothelial cells.
2018-10-24 | PXD002598 | Pride
Project description:Chronic alcohol consumption can lead to alchohol-related brain damage (ARBD). Despite the well known acute effects of alcohol the mechanism responsible for chronic brain damage is largely unknown. Pathologically the major change is the loss of white matter while neuronal loss is mild and restricted to a few areas such as the prefrontal cortex. In order to improve our understanding of ARBD pathogenesis we used microarrays to explore the white matter transcriptome of alcoholics and controls. Our results suggest that hepatic encephalopathy, along with two confounders, gray matter contamination and low RNA quality, are major drivers of gene expression in ARBD. All three exceeded the effects of alcohol itself. In particular, low quality RNA samples were characterized by an upregulation of protein translation machinery while hepatic encephalopathy was associated with a downregulation of mitochondrial energy metabolism pathways. The findings in HE alcoholics are consistent with the metabolic acidosis seen in this condition. In contrast non-HE alcoholics had widespread but only subtle changes in gene expression in their white matter. The initial cohort was compromised of four alcoholics without hepatic encephalopathy (non-HE alcoholics), three alcoholics with HE (HE alcoholics) and three neurologically normal controls. For each indvidual frozen white matter was sampled in the superior frontal gyrus (prefrontal cortex) and the precentral gyrus (motor cortex). These two cortices experience either moderate (prefrontal cortex) or no neuronal loss (motor cortex) with alcohol-related brain damage. Each white matter sample was divided in two before RNA was extracted to give two 'biological' repeats and a total of 40 samples. Subsequently eight duplicates were removed due to their gray matter contamination or low RNA quality to leave a 32-sample cohort (23 alcoholic (including eight with HE ) and nine control samples.
2014-01-04 | E-GEOD-53808 | biostudies-arrayexpress
Project description:Aging results in both grey and white matter degeneration, but the specific microglial responses are unknown. Using single-cell RNA sequencing from white and grey matter separately, we identified white matter associated microglia (WAM), which share parts of the disease-associated microglia (DAM) gene signature and are characterized by the activation of genes implicated in phagocytic activity and lipid metabolism. WAM depend on triggering receptor expressed on myeloid cells 2 (TREM2) signaling and are aging dependent. In the aged brain, WAM form independently of apolipoprotein E (APOE), which is in contrast to mouse models of Alzheimer’s disease, in which microglia with WAM gene signature are generated prematurely and in an APOE-dependent pathway similar to DAM. Within the white matter, microglia frequently cluster in nodules, where they are engaged in clearing degenerated myelin. Thus, WAM may represent a potentially protective response required to clear degenerated myelin accumulating during white matter aging and disease.
2021-02-18 | GSE166548 | GEO
Project description:Extensive reports in the past decade have shown the importance of eNOS expression in atherogenesis. However, both the eNOS knockout and overexpression mouse models exhibit paradoxical results of increased atherosclerotic lesions. Our genetic approach herein utilizes endogenous point-mutations at the eNOS S1176 site to effectively manipulate eNOS activity rather than total eNOS protein expression levels. Our efforts definitively show that eNOS S1176 phosphorylation is sufficient to mitigate atherosclerotic lesion progression.
2023-11-10 | GSE243000 | GEO
Project description:White matter aging drives microglial diversity
2021-02-08 | GSE166304 | GEO