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Early transcriptional responses post-recanalization in a mouse model of middle cerebral artery occlusion

ABSTRACT: Ischemic stroke is a leading cause of death and disability worldwide. Recanalization therapies for acute ischemic stroke, which include mechanical thrombectomy and rt-PA delivery, are limited as while the operations are successful, many patients experience poor clinical outcomes, termed futile recanalization. Using the murine middle cerebral occlusion (MCAO) model that mimics a large vessel occlusion with recanalization, we performed a comprehensive microarray analysis of blood samples post-MCAO and recanalization in male, female, young adult, and aged mice (N=44). Downstream bioinformatics analysis was then performed in RStudio. We discovered 11 hub genes that are potential genomic markers of early recanalization changes in mice. Vcan, a novel marker, is highly conserved and elevated in mice, rats, and clinical patients. Leukocyte and neutrophil functional activities have significant enrichment in both mice and humans. We identified a range of miRNAs that potentially regulated recanalization responses and NFE4 and MTF1 as the primary transcription factors. MCAO was performed MCAO mice were euthanized immediately 60 minutes after surgery. In the MCAO+Recan group, the suture was taken out 60 minutes after the onset of occlusion and mice were allowed to recover for an additional 3 hours before euthanasia. Sham mice were subjected to only anaesthesia and the manipulation of surrounding tissues and arteries.

ORGANISM(S): Mus musculus

PROVIDER: GSE278554 | GEO | 2025/10/31

REPOSITORIES: GEO

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Project description:Astrogliosis is a hallmark of the response to brain ischemia, comprised of changes in gene expression and morphology. Hsp72 protects from cerebral ischemia, and although several mechanisms of protection have been investigated, effects on astrocyte activation are unknown. To identify potential mechanisms of protection, gene expression was assessed in mice subjected to middle cerebral artery (MCAO) or sham surgery, of either wildtype (WT) or Hsp72-overexpressing (Hsp72Tg) mice. After stroke, both genotypes exhibited genes related to cell death, stress response, and immune response. Furthermore, genes indicative of astrocyte activation, including cytoskeletal proteins and cytokines, were upregulated. To measure astrocyte activation after stroke, detailed histological and morphological analyses were performed in the cortical penumbra after stroke using unbiased stereology. Consistent with other reports, we observed a marked and persistent increase in glial fibrillary acidic protein (GFAP ) as soon as 3 hours after MCAO. In contrast, vimentin immunoreactivity appeared 12-24 hours after stroke, peaked at 72 hours, and returned to baseline after 30 days. Surprisingly, no change in overall astrocyte number was observed based on glutamine synthetase (GS) immunoreactivity. To determine if Hsp72Tg mice exhibited altered astrocyte activation compared to WT controls, morphological evaluation by fractal analysis was used. Overexpression of Hsp72 reduced astrocyte cell area, arbor area, and to a lesser extent fractal dimension, 72 hours following stroke. In conclusion, in vivo overexpression of Hsp72 alters gene expression following stroke, including genes involved in astrocyte activation, and decreases astrocyte activation acutely following MCAO. Thus, modulation of astrogliosis may be a neuroprotective mechanism exerted by Hsp72 after ischemia. A total of 10 samples were analyzed, with 5 of each genotype, wildtype (WT) and Hsp72-overexpressing (Hsp72Tg) mice. Of the 5 in each group, 3 received middle cerebral artery occlusion (MCAO) and 2 received a sham surgery. The sham samples serve as the controls for the MCAO samples in each genotype. All samples were taken from the ischemic or control hemisphere 24 hours after surgery.

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Early transcriptional responses post-recanalization in a mouse model of middle cerebral artery occlusion

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