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A Rat Methyl-Seq Platform to Identify Epigenetic Changes Associated with Stress Exposure
Published on: October 24, 2018
Endothelial Cell-Specific Transcriptome Reveals Signature of Chronic Stress Related to Worse Outcome After Mild
Stephanie Wegner1, Ria Uhlemann1, Valérie Boujon1
1Klinik für Neurologie, Charité Campus Mitte, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany.
Insights
Chronic stress worsens stroke outcomes by altering brain endothelial cells. This study reveals a stress-induced transcriptomic signature in endothelial cells linked to increased stroke lesion size and impaired vascular repair mechanisms.
Area of Science:
- Neuroscience
- Vascular Biology
- Genomics
Background:
- Depression and stress negatively impact stroke outcomes through poorly understood vascular mechanisms.
- Identifying the transcriptomic profile of chronic stress in brain endothelial cells (ECs) is crucial for understanding these effects.
Purpose of the Study:
- To investigate the transcriptomic changes in cerebrovascular endothelial cells (ECs) from the ischemic brain following chronic stress.
- To elucidate the biological processes and molecular pathways affected by chronic stress in the context of ischemic stroke.
Main Methods:
- Male 129S6/SvEv mice underwent a 28-day chronic stress model.
- Ischemic lesions were induced via middle cerebral artery occlusion (MCAo) and quantified using MRI.
- RNA sequencing profiled transcriptomic changes in ECs isolated from the infarct.
Main Results:
- Chronic stress led to increased lesion volume and altered gene expression in brain ECs.
- Differentially expressed genes were enriched in pathways related to endothelial proliferation and neoangiogenesis.
- MicroRNA-34a was significantly associated with stress-induced EC changes and correlated with infarct size and Sirt1 expression.
Conclusions:
- This study provides the first EC-specific transcriptomic analysis of chronic stress in brain ischemia.
- The identified stress signature in ECs is linked to worse stroke outcomes.
- Findings highlight the role of endothelial mechanisms, including microRNA-34a and Sirt1, in the pathogenesis of stress-related stroke complications.
Abstract:
Vascular mechanisms underlying the adverse effects that depression and stress-related mental disorders have on stroke outcome are only partially understood. Identifying the transcriptomic signature of chronic stress in endothelium harvested from the ischemic brain is an important step towards elucidating the biological processes involved. Here, we subjected male 129S6/SvEv mice to a 28-day model of chronic stress. The ischemic lesion was quantified after 30 min filamentous middle cerebral artery occlusion (MCAo) and 48 h reperfusion by T2-weighted MRI. RNA sequencing was used to profile transcriptomic changes in cerebrovascular endothelial cells (ECs) from the infarct. Mice subjected to the stress procedure displayed reduced weight gain, increased adrenal gland weight, and increased hypothalamic FKBP5 mRNA and protein expression. Chronic stress conferred increased lesion volume upon MCAo. Stress-exposed mice showed a higher number of differentially expressed genes between ECs isolated from the ipsilateral and contralateral hemisphere than control mice. The genes in question are enriched for roles in biological processes closely linked to endothelial proliferation and neoangiogenesis. MicroRNA-34a was associated with nine of the top 10 biological process Gene Ontology terms selectively enriched in ECs from stressed mice. Moreover, expression of mature miR-34a-5p and miR-34a-3p in ischemic brain tissue was positively related to infarct size and negatively related to sirtuin 1 (Sirt1) mRNA transcription. In conclusion, this study represents the first EC-specific transcriptomic analysis of chronic stress in brain ischemia. The stress signature uncovered relates to worse stroke outcome and is directly relevant to endothelial mechanisms in the pathogenesis of stroke.
