Meningeal lymphatic dysfunction mediates postoperative sleep deprivation-induced cognitive decline via impaired neuroinflammatory clearance.

Postoperative sleep deprivation (PSD) exacerbates perioperative neurocognitive disorders (PND) through unresolved neuroinflammation, yet the underlying mechanisms remain elusive. Here, we aim to evaluate contribution of disregulation of the meningeal lymphatic vessels (MLVs) to PSD-induced cognitive decline. In a mosue model combining tibial fracture surgery with sleep deprivation, PSD induced spatial and contextual memory deficits, concurrent with hippocampal neuroinflammation and microglial activation. Crucially, PSD induced significant MLVs structural regression and functional impairment, which further limited drainage of inflammatory mediators (IL-1β, IL-6, and TNF-α) to deep cervical lymph nodes. Lymphatic ligation that suppressed cytokine trafficking to peripheral lymphatics amplifies hippocampal inflammation. Overexpression of vascular endothelial growth factor C (VEGF-C) by intracisternal delivery of AAV-VEGF-C to enhance MLVs function restored lymphatic drainage capacity, attenuated hippocampal neuroinflammation, and rescued PSD-induced cognitive decline. Our findings exhibit a MLVs-related pathological mechanism in PSD-related cognition impairment, showing that sleep loss disrupts meningeal lymphatic integrity, which further impairs inflammatory clearance and exaggrates neuroinflammation and neuronal dysfunction. Therapeutic targeting of restore MLVs’ function may thus offer a novel strategy to mitigate PND.