A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules

2015/06/15 by Aleksanteri Aspelund, Salli Antila, Steven T. Proulx +6 · 2,192 citations
Medicine · Neuroscience · #Anatomy #Cancer #Central nervous system #Cerebrospinal fluid #Cerebrospinal fluid and hydrocephalus #Dura mater #Glymphatic system #Internal medicine #Interstitial fluid #Interstitial space #Lymph #Lymphatic system #Lymphatic vessel #Medicine #Meninges #Pathology #Pia mater #Spinal Dysraphism and Malformations #Subarachnoid space #Traumatic Brain Injury and Neurovascular Disturbances

paper · pdf · doi:10.1084/jem.20142290

published in The Journal of Experimental Medicine 212(7), 991-999 (Rockefeller University Press)

openalex publication_date 2015/06/15 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/05

Abstract

The central nervous system (CNS) is considered an organ devoid of lymphatic vasculature. Yet, part of the cerebrospinal fluid (CSF) drains into the cervical lymph nodes (LNs). The mechanism of CSF entry into the LNs has been unclear. Here we report the surprising finding of a lymphatic vessel network in the dura mater of the mouse brain. We show that dural lymphatic vessels absorb CSF from the adjacent subarachnoid space and brain interstitial fluid (ISF) via the glymphatic system. Dural lymphatic vessels transport fluid into deep cervical LNs (dcLNs) via foramina at the base of the skull. In a transgenic mouse model expressing a VEGF-C/D trap and displaying complete aplasia of the dural lymphatic vessels, macromolecule clearance from the brain was attenuated and transport from the subarachnoid space into dcLNs was abrogated. Surprisingly, brain ISF pressure and water content were unaffected. Overall, these findings indicate that the mechanism of CSF flow into the dcLNs is directly via an adjacent dural lymphatic network, which may be important for the clearance of macromolecules from the brain. Importantly, these results call for a reexamination of the role of the lymphatic system in CNS physiology and disease.

Cited by

• Fluorescence imaging of lymphatic outflow of cerebrospinal fluid in mice
• VEGF-C prophylaxis favors lymphatic drainage and modulates neuroinflammation in a stroke model
• Differential impact of lymphatic outflow pathways on cerebrospinal fluid homeostasis
• Lymphatic transport in anti-tumor immunity and metastasis
• A human brain vascular atlas reveals diverse mediators of Alzheimer’s risk
• The adaptive immune system in the retina of diabetics
• Meningeal lymphatics-microglia axis regulates synaptic physiology
• Blood-Brain Barrier: From Physiology to Disease and Back
• Cerebrospinal Fluid Flow
• Geometry Reduced Order Modeling (GROM) with application to modeling of glymphatic function
• Immune control of brain physiology
• Perivascular spaces in the brain: anatomy, physiology and pathology
• Melatonin regulates Aβ production/clearance balance and Aβ neurotoxicity: A potential therapeutic molecule for Alzheimer’s disease
• Contrast‐Enhanced Fluid‐Attenuated Inversion Recovery in Neuroimaging: A Narrative Review on Clinical Applications and Technical Advances
• Anatomical and Molecular Characterization of the Zebrafish Meninges
• ENDOTHELIAL PROX1 INDUCES BLOOD-BRAIN BARRIER DISRUPTION IN THE CENTRAL NERVOUS SYSTEM
• Lymphatic dysfunction correlates with inflammation in a mouse model of amyotrophic lateral sclerosis
• Astrocytes in the regulation of cerebrovascular functions
• Waste clearance shapes aging brain health
• Dual role of vascular endothelial growth factor-C in post-stroke recovery
• Glymphatic failure as a final common pathway to dementia
• Sleep deprivation leads to non-adaptive alterations in sleep microarchitecture and amyloid-β accumulation in a murine Alzheimer model
• Glutathione metabolism-related gene signature predicts prognosis and treatment response in low-grade glioma
• Meningeal blood vessel blockage enhances anti-glioblastoma immunity
• Identification of lymphatic vessels in skull periosteum but not bone marrow reveals skull channel heterogeneity
• Morphology of the glymphatic and meningeal lymphatic structures of the bottlenose dolphin
• Inflammation in CNS neurodegenerative diseases
• The Brain’s Glymphatic System: Current Controversies
• Fluid transport in the brain
• Targeting macrophages in cancer immunotherapy
• Loss of meningeal lymphatic endothelial cells results in formation of a newly forming vascular network with scavenging function
• Endothelial PROX1 induces blood-brain barrier disruption in the central nervous system
• The blood–CSF–brain route of neurological disease: The indirect pathway into the brain
• Therapeutic Targeting of the Tumor Microenvironment
• Perivascular spaces, glymphatic dysfunction, and small vessel disease
• Fluid and ion transfer across the blood–brain and blood–cerebrospinal fluid barriers; a comparative account of mechanisms and roles
• The emerging importance of lymphangiogenesis in aging and aging-associated diseases
• Defining novel functions for cerebrospinal fluid in ALS pathophysiology
• Proton therapy reduces the likelihood of high-grade radiation-induced lymphopenia in glioblastoma patients: phase II randomized study of protons vs photons
• The Relationship between Obstructive Sleep Apnea and Alzheimer’s Disease
• Our current understanding of the lymphatics of the brain and spinal cord
• Glymphatic-meningeal lymphatic dysfunction drives remote organ injury after aneurysmal subarachnoid hemorrhage: a unified neuroimmune framework and time-stratified therapeutic roadmap
• Revisiting the Mechanisms of CNS Immune Privilege. [europepmc]
• Establishment and Dysfunction of the Blood-Brain Barrier. [europepmc]
• The Central Nervous System and the Gut Microbiome. [europepmc]
• The far-reaching scope of neuroinflammation after traumatic brain injury. [europepmc]
• The Microenvironmental Landscape of Brain Tumors. [europepmc]
• Understanding the functions and relationships of the glymphatic system and meningeal lymphatics. [europepmc]
• Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI. [europepmc]
• Outflow of cerebrospinal fluid is predominantly through lymphatic vessels and is reduced in aged mice. [europepmc]
• The Glymphatic System in Central Nervous System Health and Disease: Past, Present, and Future. [europepmc]
• Physiology of Astroglia. [europepmc]
• Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. [europepmc]
• Functional aspects of meningeal lymphatics in ageing and Alzheimer's disease. [europepmc]
• Direct vascular channels connect skull bone marrow and the brain surface enabling myeloid cell migration. [europepmc]
• CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature. [europepmc]
• Blood-Brain Barrier: From Physiology to Disease and Back. [europepmc]
• The glymphatic pathway in neurological disorders. [europepmc]
• Aquaporin-4-dependent glymphatic solute transport in the rodent brain. [europepmc]
• Brain immunology and immunotherapy in brain tumours. [europepmc]
• The Brain's Glymphatic System: Current Controversies. [europepmc]
• The Lymphatic Vasculature in the 21 st Century: Novel Functional Roles in Homeostasis and Disease. [europepmc]
• Glymphatic failure as a final common pathway to dementia. [europepmc]
• The Gut-Brain Axis: How Microbiota and Host Inflammasome Influence Brain Physiology and Pathology. [europepmc]
• Functional characterization of the dural sinuses as a neuroimmune interface. [europepmc]
• Targeting macrophages in cancer immunotherapy. [europepmc]
• A human brain vascular atlas reveals diverse mediators of Alzheimer's risk. [europepmc]

Related

• Our current understanding of the lymphatics of the brain and spinal cord
• Differential impact of lymphatic outflow pathways on cerebrospinal fluid homeostasis
• Anatomy of the vertebral column lymphatic network in mice
• CSF drains directly from the subarachnoid space into nasal lymphatics in the rat. Anatomy, histology and immunological significance
• Loss of meningeal lymphatic endothelial cells results in formation of a newly forming vascular network with scavenging function