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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. [ABSTRACT FROM AUTHOR]

Two fundamental concepts have impeded the development of research in brain, behavior and immunity during the past century. They have been presented in neuroscience textbooks since the beginning of the 20th century. Recent discoveries require that both views are in serious need of being updated in the scientific literature and medical textbooks. These two age‐old concepts are lack of lymphatic drainage in the brain and immune privilege of the central nervous system associated with impermeability of the blood–brain barrier. [ABSTRACT FROM AUTHOR]

Background: Traditionally, the central nervous system (CNS) has been viewed as an immune‐privileged environment with no lymphatic vessels. This view was partially overturned by the discovery of lymphatic vessels in the dural membrane that surrounds the brain, in contact with the interior surface of the skull. We here examine the distribution and developmental timing of these lymphatic vessels. Results: Using the Prox1‐GFP BAC transgenic reporter and immunostaining with antibodies to lymphatic markers LYVE‐1, Prox1, and Podoplanin, we have carried out whole‐mount imaging of dural lymphatic vasculature at postnatal stages. We have found that between birth and postnatal day (P) 13, lymphatic vessels extend alongside dural blood vessels from the side of the skull toward the midline. Between P13 and P20, lymphatic vessels along the transverse sinuses reach the superior sagittal sinus (SSS) and extend along the SSS toward the olfactory bulb. Conclusions: Compared with the embryonic developmental timing of lymphatic vessels in other tissues, e.g. skin, dural lymphatic vessel development is dramatically delayed. This study provides useful anatomical data for continuing investigations of the fundamental mechanisms that underlie dural lymphatic vessel development. Developmental Dynamics 247:741–753, 2018. © 2018 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]