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.脑白质高信号（White matter hyperintensity, WMH）是一项亟待破解的全球性医学难题，与认知衰退及卒中风险紧密相关。尽管其临床意义重大，但该病变的潜在发病机制仍未明确。本研究首次在人体中证实，高负荷WMH与胶质淋巴通路引流延迟存在显著相关性；此外，一项纵向队列研究揭示，胶质淋巴功能障碍可预测WMH的疾病进展。随后，在WMH大鼠模型中，我们验证了淋巴管生成与胶质淋巴引流受损的病理现象，并观察到小胶质细胞激活加剧及脑白质脱髓鞘。值得注意的是，通过腺病毒递送血管内皮生长因子C（Vascular Endothelial Growth Factor-C, VEGF-C）以增强脑膜淋巴管生成与胶质淋巴引流，可有效缓解小胶质细胞胶质增生与脑白质脱髓鞘；反之，采用VEGF-C陷阱策略阻断脑膜淋巴管生成，则会加重上述病理改变。本研究结果明确了脑膜淋巴管功能异常与胶质淋巴通路障碍在加重脑白质损伤、促进WMH进展中的关键作用，为WMH的预防与治疗提供了潜在的全新干预策略。