Endothelial Cell-Specific Transcriptome Reveals Signature of Chronic Stress Related to Worse Outcome After Mild Transient Brain Ischemia in Mice
Endothelial Cell-Specific Transcriptome Reveals Signature of Chronic Stress Related to Worse Outcome After Mild Transient Brain Ischemia in Mice
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DOI：
10.1007/s12035-019-01822-3
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发表时间：
2019-11-22
影响因子：
5.1
通讯作者：
Gertz, Karen
中科院分区：
文献类型：
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作者：
Wegner, Stephanie;Uhlemann, Ria;Gertz, Karen
抑郁症和应激相关精神障碍对卒中结局的不良影响的血管机制仅部分了解。鉴定从缺血脑中收获的内皮细胞中慢性应激的转录组学特征是阐明所涉及的生物学过程的重要一步。在这里，我们将雄性129 S6/SvEv小鼠置于28天的慢性应激模型中。大脑中动脉缺血30 min后再灌注48 h，采用T2加权MRI对缺血性病变进行定量。RNA测序被用来分析梗死后脑血管内皮细胞（EC）的转录组学变化。经受应激程序的小鼠显示体重增加减少、肾上腺重量增加以及下丘脑FKBP 5 mRNA和蛋白表达增加。慢性应激增加了MCAo的病变体积。与对照小鼠相比，应激小鼠从同侧和对侧半球分离的EC之间显示出更高数量的差异表达基因。所讨论的基因在与内皮细胞增殖和新血管生成密切相关的生物过程中发挥作用。MicroRNA-34 a与前10个生物过程中的9个相关，基因本体论术语选择性地富集在来自应激小鼠的EC中。此外，缺血脑组织中成熟miR-34 a-5 p和miR-34 a-3 p的表达与梗死面积呈正相关，与sirtuin 1（Sirt 1）mRNA转录呈负相关。总之，这项研究代表了脑缺血慢性应激的第一个EC特异性转录组学分析。暴露的应激信号与更差的卒中结局有关，并且与卒中发病机制中的内皮机制直接相关。
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.