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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. Electronic supplementary material The online version of this article (10.1007/s12035-019-01822-3) contains supplementary material, which is available to authorized users.