title: A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules.
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.
authors.affiliation: Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, 00014 Helsinki, Finland Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Aleksanteri
authors.initials: A
authors.lastname: Aspelund
authors.affiliation: Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, 00014 Helsinki, Finland Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Salli
authors.initials: S
authors.lastname: Antila
authors.affiliation: Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH Zurich), CH-8093 Zurich, Switzerland.
authors.forename: Steven T
authors.initials: ST
authors.lastname: Proulx
authors.affiliation: Department of Biomedicine, University of Bergen, 5009 Bergen, Norway.
authors.forename: Tine Veronica
authors.initials: TV
authors.lastname: Karlsen
authors.affiliation: Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH Zurich), CH-8093 Zurich, Switzerland.
authors.forename: Sinem
authors.initials: S
authors.lastname: Karaman
authors.affiliation: Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH Zurich), CH-8093 Zurich, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Detmar
authors.affiliation: Department of Biomedicine, University of Bergen, 5009 Bergen, Norway.
authors.forename: Helge
authors.initials: H
authors.lastname: Wiig
authors.affiliation: Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, 00014 Helsinki, Finland Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, 00014 Helsinki, Finland kari.alitalo@helsinki.fi.
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism*; D002555:Cerebrospinal Fluid / Q000378:metabolism*; D045604:Extracellular Fluid / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D005697:Galactosides; D049452:Green Fluorescent Proteins; D007091:Image Processing, Computer-Assisted; D007211:Indoles; D008198:Lymph Nodes / Q000378:metabolism*; D008208:Lymphatic System / Q000033:anatomy & histology / Q000378:metabolism*; D046911:Macromolecular Substances / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal
chemical_list: D005697:Galactosides; D007211:Indoles; D046911:Macromolecular Substances; D049452:Green Fluorescent Proteins; C044888:5-bromo-4-chloro-3-indolyl beta-galactoside