Enhanced meningeal lymphangiogenesis and glymphatic drainage ameliorates neuroinflammation and white matter demyelination

White matter hyperintensity (WMH) is a pressing global medical issue linked to cognitive decline and stroke risk. Despite its significance, the underlying mechanisms remain unclear. Here, we directly demonstrated in humans that high WMH burden correlated with delayed glymphatic pathway drainage. Additionally, a longitudinal cohort study revealed that glymphatic dysfunction predicted WMH progression. Next, in a rat model of WMH, we confirmed the presence of impaired lymphangiogenesis and glymphatic drainage, followed by elevated microglial activation and white matter demyelination. Notably, enhancing meningeal lymphangiogenesis and glymphatic drainage through adenoviral delivery of Vascular Endothelial Growth Factor-C (VEGF-C) mitigated microglial gliosis and white matter demyelination. Conversely, blocking the growth of meningeal lymphatics with a VEGF-C trap strategy exacerbated these changes. Our findings highlight the role of meningeal lymphatics and glymphatic pathway dysfunction in aggravating brain white matter injury and advancing WMH, providing a potential novel strategy for WMH prevention and treatment. Overall design: RNA-sequencing data of corpus callosum from Spontaneously hypertensive rats (SHR), Wistar Kyoto rats (WKY), AAV2/9-CMV-rVEGF-C treated SHR and AAV2/9-CMV-mNeonGreen (as control)treated SHR.