Abstract Body: Vascular normalization and restoration of blood-brain barrier (BBB) function are critical to reestablish a microenvironment that supports tissue repair and functional recovery after ischemic stroke. During development, central nervous system (CNS) angiogenesis and barriergenesis are coupled via canonical Wnt/β-catenin signaling. Following ischemic insult, brain endothelial cells (BECs) upregulate Wnt signaling on a background of acute inflammation. How distinct immune signaling pathways cooperate with developmental pathways to differentially regulate and temporally coordinate post-stroke vascular remodeling remains poorly understood. Here, we identify a unique BEC type I interferon (IFNI) signature in human and mouse ischemic stroke tissue using immunohistochemistry and RNA in situ hybridization. By leveraging two clinically relevant murine ischemic stroke models, single-cell transcriptomic technology, and Biocytin-TMR tracer leakage assays, we identify that genetic deletion of endothelial IFNI receptor (IFNAR1) exacerbates post-stroke barrier disruption and results in an expansion of BECs characterized by marker genes associated with angiogenesis and immature BBB. Conversely, acute administration of exogenous IFNI ameliorates post-stroke BBB disruption. Functional in vitro assays (trans-endothelial electrical resistance / wound healing) and western blotting reveal that BEC IFNI signaling modulates VE-Cadherin stabilization and vascular endothelial growth factor (VEGF) signaling to enhance BEC barrier properties and suppress angiogenic features, respectively. Together, our work supports that endogenous BEC IFNI signaling regulates acute BEC function after ischemic brain injury through the 1) restriction of angiogenesis onset and/or 2) augmentation of vascular maturation to promote barrier function. Moreover, these findings may have broader implications for understanding CNS vascular pathology and normalization in the setting of brain states characterized by acute (i.e. stroke, traumatic brain injury) or chronic (i.e. multiple sclerosis, neurodegeneration, aging) sterile inflammation.