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Cerebrovascular injuries can cause severe edema and inflammation that adversely affect human health. Here, we observed that 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 an 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 subsequently orchestrated by proinflammatory monocytes and proangiogenic repair-associated microglia (RAM). These data

demonstrate how temporally distinct myeloid cell responses can contain, exacerbate and ultimately repair a cerebrovascular injury.

The data that support the findings of this study are available from the corresponding author upon request. There are no restrictions on data availability. Bulk RNA-seq data are available in

the NCBI Gene Expression Omnibus under accession code GSE161424. Source data are provided with this paper.

This research was supported by the intramural program at the NINDS, NIH. We thank A. Hoofring in the NIH Medical Arts Design Section for generating the illustration shown in Extended Data

Fig. 1. We thank A. Elkahloun and W. Wu in the National Human Genome Research Institute Microarray core for their assistance with the RNA-seq experiment.

Viral Immunology & Intravital Imaging Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA

Department of Surgical Neurology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA

Acute Cerebrovascular Diagnostics Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA

Frank Laboratory, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, USA

National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA

MedStar Washington Hospital Center Comprehensive Stroke Center, Washington, DC, USA

National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD, USA

P.M. and N.M. performed the data acquisition and analysis. P.M., M.L., A.W.H. and L.L. contributed to the design, acquisition and analysis of clinical data. S.R.B., J.W. and J.A.F.

contributed to optimization of the ultrasound model and performed the mouse MRI studies. K.J. conducted computation analyses of RNA-seq data. P.M. and D.B.M. wrote and edited the manuscript.

D.B.M. supervised and directed the project and participated in data acquisition and analysis.

Peer review information Nature Neuroscience thanks Thiruma Arumugam, Jonathan Godbout, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Following surgical generation of a 2 mm x 2 mm x 15 µm thinned skull window, microbubbles were injected intravenously and a drop of aCSF was placed atop the thinned skull bone. Through this

aCSF we applied low intensity pulse ultrasound (LIPUS) using a Mettler Sonicator 740x with a 5 cm2 planar dual frequency applicator operating at 1 MHz, ~200KPa peak negative pressure with

duty cycle 10% and 1 ms burst. LIPUS induced acoustic cavitation of the microbubbles. Microbubble oscillation, inertial cavitation, and explosion caused internal injury of blood vessel

walls, exposing the brain parenchyma to blood contents. This injury creates a relative column of injury in the brain tissue beneath the thinned skull window, as the ultrasound waves are not

strong enough to pass through the surrounding intact bone.

a, Magnified images of the 2 mm x 2 mm x 15 µm thinned skull window pre- and post-injury depict petechial intraparenchymal hemorrhages at 10 min post-injury. b, Macroscopic depiction of a

mouse brain 24 h following posterior sonication injury. c, Kaplan-Meier curve demonstrates a median survival of 2 days after posterior sonication injury. Anterior sonication injury does not

result in fatalities. Cumulative data are shown from 2 independent experiments with 10 mice per group (P = 2.96e-10, Log-rank test). d, A graph showing quantification of cerebral water

content demonstrates increased edema 24 h after sonication with 7.7% and 7.1% increase in water content after anterior and posterior injury, respectively, relative to uninjured control mice

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