6E,?,F).F). Availability StatementData availability The data that support the findings of this study are available from the corresponding author upon request. There are no restrictions in data availability. The following figures have associated source data in the supplementary section: Figures 1C, ?,1D,1D, ?,2D,2D, ?,2G,2G, ?,2H,2H, ?,2I,2I, ?,3C,3C, ?,3E,3E, ?,3F,3F, ?,3G,3G, ?,3H,3H, ?,3I,3I, ?,4B,4B, ?,4D,4D, ?,4F,4F, ?,4H,4H, Tyk2-IN-7 ?,4H,4H, ?,5A,5A, ?,5D,5D, ?,5F,5F, ?,5H,5H, ?,6E,6E, ?,6F6F Extended Data Figures 2D, ?,2E,2E, ?,2H,2H, ?,3B,3B, ?,3D,3D, ?,3F,3F, ?,3H,3H, ?,6A,6A, ?,6B,6B, ?,6C,6C, ?,6D,6D, ?,7A,7A, ?,7B,7B, ?,7C,7C, ?,7E,7E, ?,7F,7F, ?,7G,7G, ?,8C,8C, ?,8D,8D, ?,8F,8F, 10B. Bulk RNA sequencing data are available in the NCBI Gene Expression Omnibus. Abstract Cerebrovascular injuries can cause severe edema Rabbit Polyclonal to USP32 and inflammation that adversely affect human health. Here, we observed recanalization after successful endovascular thrombectomy for acute large vessel occlusion was associated with cerebral edema and poor clinical outcomes in patients who experienced hemorrhagic transformation. To understand this process, we developed a cerebrovascular injury model using transcranial ultrasound that enabled spatiotemporal evaluation of resident and peripheral myeloid cells. We discovered that injurious and reparative responses diverged based on time and cellular origin. Resident microglia initially stabilized damaged vessels in a purinergic receptor-dependent manner, which was followed by influx of myelomonocytic cells that caused severe edema. Prolonged blockade of myeloid cell recruitment with anti-adhesion molecule therapy prevented severe edema but also promoted neuronal destruction and fibrosis by interfering with vascular repair later orchestrated by pro-inflammatory monocytes and pro-angiogenic repair-associated microglia (RAM). These data demonstrate how temporally distinct myeloid cell responses can contain, exacerbate, and ultimately repair a cerebrovascular injury. Introduction The cerebral vasculature is usually sealed by a barrier system that isolates the central nervous system (CNS) from the systemic circulation1. The blood brain barrier (BBB) is usually comprised of endothelial cells, basement membrane, pericytes, and glia limitans that control the exchange of cells and substances between the CNS and circulation. CNS vasculature are susceptible, however, to damage resulting from mechanical forces, degenerative processes, and ischemia. Cerebrovascular diseases Tyk2-IN-7 can have devastating outcomes, which is usually Tyk2-IN-7 exemplified by ischemic disorders like strokes – the second leading cause of death and the leading cause of disability in humans worldwide2. The importance of cerebral vasculature in maintaining CNS homeostasis is usually exemplified by the adverse effects associated with other barrier disruptive disorders, including traumatic brain injury (TBI), primary intracranial hemorrhage (ICH), and hemorrhagic transformation following stroke. For example, TBI can substantially disrupt the cerebrovascular network by widening of intercellular junctions between endothelial cells and promoting swelling of perivascular astrocytes as well as hemorrhage3. Vasogenic edema is usually another contributor to secondary damage following vascular injury and can induce cerebral herniation C a potentially fatal condition resulting from fluid-induced compression Tyk2-IN-7 of brain tissue4. Following ischemic stroke, the initial injury is usually attributed to reduced regional cerebral blood flow5,6. However, secondary damage can occur upon vascular reperfusion, such as BBB breakdown, hemorrhagic transformation, and severe brain swelling associated with invasion by peripheral myelomonocytic cells5,7C10. Vascular damage is usually a feature of many CNS pathologies, but most TBI and stroke models evaluate net outcomes of multiple injurious processes and attempt to extrapolate the contribution of vascular damage to these outcomes. Consequently, the isolated contribution of cerebrovascular disruption and subsequent leakage of materials from the blood into the CNS is not well understood. To better understand this process, we developed a model of isolated cerebrovascular injury using a combination of ultrasound and intravenously (i.v.) injected microbubbles that allowed us to apply injurious mechanical forces to select beds of brain vasculature. We then used this model to study the complete spatiotemporal progression of the injurious process, from the initial moments following vascular damage to the induction of angiogenic repair programming and subsequent restoration of neurological function. Results Intraparenchymal hemorrhage is usually associated with cerebral edema Intraparenchymal hemorrhage is usually associated with TBI, ICH, and stroke. Evaluation of these patients by magnetic resonance imaging (MRI) revealed that intraparenchymal hemorrhage promotes T2-FLAIR hyperintensities that surround the hemorrhagic lesion C a pattern consistent with the development of edema (Fig. 1A). To gain additional insights into this pathological process, we focused on patients that develop cerebrovascular hemorrhage and edema on a more defined time scale. Specifically, we evaluated 30 patients with large vessel occlusion acute ischemic stroke who underwent endovascular thrombectomy (EVT), with largely successful recanalization (87% with TICI 2b/3) (Supplementary Table 1). In this cohort, 16 patients had no hemorrhage after embolectomy, 6 had hemorrhagic infarction (petechial blood), and 8 had parenchymal.
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