Multiple sevoflurane exposures in early development lead to long-term vascular abnormalities in the hippocampus

Abstract Children who undergo multiple exposures to anesthesia for surgeries and procedures are at increased risk of developing neurocognitive impairments. Growing evidence suggests that anesthesia-induced neurotoxicity and acute damage to neural cells underlie these impairments. However, the mechanisms underlying the long-term adverse effects of early anesthetic exposure remain largely unknown. Here, we show that repeated early-life exposures to sevoflurane, a commonly used anesthetic in clinical practice, lead to long-term impairments in hippocampal vascular architecture, characterized by reduced vascular area and branching complexity, associated with alterations in postsynaptic density composition. Mechanistically, sevoflurane exposure was associated with evidence of impaired endothelial cell integrity and elevated circulating levels of the pro-inflammatory cytokine TNF-α. In vitro, physiologically relevant concentrations of TNF-α potentiated sevoflurane-induced endothelial cell injury, indicating that inflammatory signaling may exacerbate endothelial vulnerability. Together, these findings identify microvascular regression as a long-term consequence of early anesthetic exposure and suggest that preservation of endothelial integrity may represent a therapeutic strategy to mitigate or prevent anesthesia-associated neurodevelopmental risk. Graphical Abstract • Repeated early-life exposure to sevoflurane elevates plasma TNF-α levels. • Sevoflurane exposure reduces CD31 expression in hippocampal microvasculature. • The combination of elevated TNF-α and endothelial vulnerability promotes vascular regression. • Vascular regression is associated with reduced postsynaptic density.