Cerebral small vessel injury in mice with damage to ACE2‐expressing cerebral vascular endothelial cells and post COVID‐19 patients

INTRODUCTION The angiotensin‐converting enzyme 2 (ACE2), which is expressed in cerebral vascular endothelial cells (CVECs), has been currently identified as a functional receptor for SARS‐CoV‐2. METHODS We specifically induced injury to ACE2‐expressing CVECs in mice and evaluated the effects of such targeted damage through magnetic resonance imaging (MRI) and cognitive behavioral tests. In parallel, we recruited a single‐center cohort of COVID‐19 survivors and further assessed their brain microvascular injury based on cognition and emotional scales, cranial MRI scans, and blood proteomic measurements. RESULTS Here, we show an array of pathological and behavioral alterations characteristic of cerebral small vessel disease (CSVD) in mice that targeted damage to ACE2‐expressing CVECs, and COVID‐19 survivors. These CSVD‐like manifestations persist for at least 7 months post‐recovery from COVID‐19. DISCUSSION Our findings suggest that SARS‐CoV‐2 may induce cerebral small vessel damage with persistent sequelae, underscoring the imperative for heightened clinical vigilance in mitigating or treating SARS‐CoV‐2‐mediated cerebral endothelial injury throughout infection and convalescence. Highlights Cerebral small vessel disease–associated changes were observed after targeted damage to angiotensin‐converting enzyme 2–expressing cerebral vascular endothelial cells. SARS‐CoV‐2 may induce cerebral small vessel damage with persistent sequelae. Clinical vigilance is needed in preventing SARS‐CoV‐2–induced cerebral endothelial damage during infection and recovery.