Impaired Meningeal Lymphatics and Glymphatic Pathway in Patients with White Matter Hyperintensity

White matter hyperintensity (WMH) represents a critical global medical concern linked to cognitive decline and dementia, yet its underlying mechanisms remain poorly understood. Here, humans are directly demonstrated that high WMH burden correlates with delayed drainage of meningeal lymphatic vessels (mLVs) and glymphatic pathway. Additionally, a longitudinal cohort study reveals that glymphatic dysfunction predicts WMH progression. Next, in a rat model of WMH, the presence of impaired lymphangiogenesis and glymphatic drainage is confirmed, followed by elevated microglial activation and white matter demyelination. Notably, enhancing meningeal lymphangiogenesis through adeno‐associated virus delivery of vascular endothelial growth factor‐C (VEGF‐C) mitigates microglial gliosis and white matter demyelination. Conversely, blocking the growth of mLVs with a VEGF‐C trap strategy exacerbates these changes. The findings highlight the role of mLVs and glymphatic pathway dysfunction in aggravating brain white matter injury, providing a potential novel strategy for WMH prevention and treatment. Patients with a high burden of white matter hyperintensities are found to have impaired drainage in the meningeal lymphatic vessels and glymphatic pathway. Enhanced meningeal lymphatic vessels and glymphatic pathway drainage via adenoviral delivery of vascular endothelial growth factor‐C ameliorate white matter damage. Improvement of meningeal lymphatic vessels and glymphatic pathway function may offer a promising strategy for delaying or even preventing the progression of white matter hyperintensities.