ABSTRACT COVID-19, which is caused by Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2), has resulted in devastating morbidity and mortality worldwide due to lethal pneumonia and respiratory distress. In addition, the central nervous system (CNS) is well documented to be a target of SARS-CoV-2, and studies detected SARS-CoV-2 in the brain and the cerebrospinal fluid of COVID-19 patients. An increased spread of emerging SARS-CoV-2 variants, such as delta or omicron, appears to be the result of a fitness advantage rather than founder effects and/or genetic drift; therefore, similar trends are expected to continue in the future. While respiratory distress dominates acute clinical symptoms of COVID-19, neurological and cerebrovascular symptoms play a critical role in so called “long-COVID” or chronic COVID. However, the interactions of SARS- CoV-2 with the brain microvasculature and how they predispose to ischemic stroke are largely unknown. The current proposal aims to close this gap of knowledge by its focus on the impact of SARS-CoV-2 on brain microvessels and by focusing on a long-term impact of the infection. The proposal is based on the central hypothesis that SARS-CoV-2 S1 protein affects the integrity of the brain microvessels and affects stroke development via inflammatory responses and epigenetic dysregulation of cerebral microvascular integrity. This hypothesis is novel, and the proposed studies are likely to generate unique data sets. As the result of substantial financial investments, we completed RNA-Seq analyses of transcriptomics signatures of human brain microvascular endothelial cells (HBMEC) infected with SARS-CoV-2. The obtained data allowed us to identify several genes and pathways, which most significantly contribute to SARS-CoV-2-induced cerebral microvascular pathology. The proposal is built on these results. Specifically, we will explore the role of epigenetic regulators in SARS-CoV-2-induced cerebrovascular dysfunction, hyperinflammatory reactions, and ischemic stroke. The impact of SARS-CoV-2 on the cerebral vasculature is largely unknown, making the proposed studies truly innovative. Knowledge of the underlying mechanism(s) of SARS-CoV-2-induced microvascular disruption may provide targets for pharmacological intervention to protect against viral entry into the brain and devastating cerebrovascular pathologies associated with COVID-19 and, especially with a chronic form of this disease. Thus, the outcome of this proposal will provide critically important and therapeutically-relevant information on the involvement of the cerebrovasculature in COVID-19 pathology.