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

Aspelund A, Antila S, Proulx ST, Karlsen TV, Karaman S, Detmar M, Wiig H, Alitalo K - J. Exp. Med. (2015)

Bottom Line: 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.

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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.

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Dura mater lymphatic vessels drain brain ISF into dcLNs. (A–J) Analysis of lymphatic outflow routes of cerebral ISF by fluorescent stereomicroscopy in Prox1-GFP (green) mice 1 h after PEG-IRDye (red) injection into the brain parenchyma without (A–F) and with (G–J) ligation of the efferent lymphatic vessel of the dcLN. See K for schematic illustration of the experimental setup and summary of the results with and without ligation. (A and B) dcLNs and scLNs (both indicated with arrowheads) showing preferential filling of the ipsilateral dcLN but no filling in the scLNs. (C) Drainage into the ipsilateral dcLN via the efferent carotid lymphatic vessels (arrowheads). CCA, common carotid artery. (D) Internal carotid artery (ICA) and adjacent lymphatic vessels (white arrowheads) immediately below the osseous skull, showing drainage from the skull (yellow arrowhead). (E and F) Lymphatic vessels around the pterygopalatine artery (PPA), showing tracer uptake by the dura mater lymphatic vessels (arrowheads) only in the basal parts of the skull, nearby their exit site. MMA, middle meningeal artery. (G) Placement of a suture around the efferent lymphatic vessel (asterisk) of the dcLN. Arrowheads, afferent lymphatic vessels. (H) Afferent lymphatic vessel of the dcLN after ligation (asterisk), showing bulging of the afferent vessels (arrowheads). (I and J) Lymphatic vessels around the posterior branch of the MMA, showing increased filling of lymphatic vessels after ligation, extending above the retroglenoid vein (RGV) level. n = 2–3/group. Data are representative of two independent experiments. Bars: (A–E and G–J) 500 µm; (F) 100 µm.
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fig2: Dura mater lymphatic vessels drain brain ISF into dcLNs. (A–J) Analysis of lymphatic outflow routes of cerebral ISF by fluorescent stereomicroscopy in Prox1-GFP (green) mice 1 h after PEG-IRDye (red) injection into the brain parenchyma without (A–F) and with (G–J) ligation of the efferent lymphatic vessel of the dcLN. See K for schematic illustration of the experimental setup and summary of the results with and without ligation. (A and B) dcLNs and scLNs (both indicated with arrowheads) showing preferential filling of the ipsilateral dcLN but no filling in the scLNs. (C) Drainage into the ipsilateral dcLN via the efferent carotid lymphatic vessels (arrowheads). CCA, common carotid artery. (D) Internal carotid artery (ICA) and adjacent lymphatic vessels (white arrowheads) immediately below the osseous skull, showing drainage from the skull (yellow arrowhead). (E and F) Lymphatic vessels around the pterygopalatine artery (PPA), showing tracer uptake by the dura mater lymphatic vessels (arrowheads) only in the basal parts of the skull, nearby their exit site. MMA, middle meningeal artery. (G) Placement of a suture around the efferent lymphatic vessel (asterisk) of the dcLN. Arrowheads, afferent lymphatic vessels. (H) Afferent lymphatic vessel of the dcLN after ligation (asterisk), showing bulging of the afferent vessels (arrowheads). (I and J) Lymphatic vessels around the posterior branch of the MMA, showing increased filling of lymphatic vessels after ligation, extending above the retroglenoid vein (RGV) level. n = 2–3/group. Data are representative of two independent experiments. Bars: (A–E and G–J) 500 µm; (F) 100 µm.

Mentions: Tracers injected into the brain ISF have been shown to translocate into the CSF via the glymphatic system and further into dcLNs (Koh et al., 2005; Iliff et al., 2012; Plog et al., 2015). However, it is unclear how these tracers gain access into the LNs. We hypothesized that the dura mater lymphatic vessels absorb brain ISF and CSF. To test this, we injected an inert 20-kD poly(ethylene glycol) (PEG) conjugate of the bright near-infrared dye IRDye 680 (PEG-IRDye; Proulx et al., 2013) into the brain parenchyma of the Prox1-GFP mice. 2 h after injection, the tracer was observed to exit the brain via paravenous routes for entry into the CSF space (not depicted), as previously reported (Iliff et al., 2012). Lymphatic drainage of brain ISF was confirmed by visualization of an intense signal in the dcLN but not in the superficial cervical LNs (scLNs; Fig. 2, A and B). Preferential drainage into the dcLN ipsilateral to the side of injection was observed (Fig. 2, A and C). When the tracer-filled afferent lymphatic vessels of the dcLNs were followed upstream, the vessels appeared to drain from the base of the skull (Fig. 2, C and D). Inside the skull, some PEG-IRDye filling of dura mater lymphatic vessels was observed only in the basal parts of the skull (Fig. 2, E and F), suggesting uptake by the lymphatic vessels but a quick washout. When the efferent lymphatic vessel of the dcLN was ligated (Fig. 2, G and H), enhanced filling of the dural lymphatic vessels was observed (Fig. 2, I–K). These data suggest that the dura mater lymphatic vessels absorb brain ISF/CSF from the subarachnoid space for transport into downstream dcLNs.


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

Aspelund A, Antila S, Proulx ST, Karlsen TV, Karaman S, Detmar M, Wiig H, Alitalo K - J. Exp. Med. (2015)

Dura mater lymphatic vessels drain brain ISF into dcLNs. (A–J) Analysis of lymphatic outflow routes of cerebral ISF by fluorescent stereomicroscopy in Prox1-GFP (green) mice 1 h after PEG-IRDye (red) injection into the brain parenchyma without (A–F) and with (G–J) ligation of the efferent lymphatic vessel of the dcLN. See K for schematic illustration of the experimental setup and summary of the results with and without ligation. (A and B) dcLNs and scLNs (both indicated with arrowheads) showing preferential filling of the ipsilateral dcLN but no filling in the scLNs. (C) Drainage into the ipsilateral dcLN via the efferent carotid lymphatic vessels (arrowheads). CCA, common carotid artery. (D) Internal carotid artery (ICA) and adjacent lymphatic vessels (white arrowheads) immediately below the osseous skull, showing drainage from the skull (yellow arrowhead). (E and F) Lymphatic vessels around the pterygopalatine artery (PPA), showing tracer uptake by the dura mater lymphatic vessels (arrowheads) only in the basal parts of the skull, nearby their exit site. MMA, middle meningeal artery. (G) Placement of a suture around the efferent lymphatic vessel (asterisk) of the dcLN. Arrowheads, afferent lymphatic vessels. (H) Afferent lymphatic vessel of the dcLN after ligation (asterisk), showing bulging of the afferent vessels (arrowheads). (I and J) Lymphatic vessels around the posterior branch of the MMA, showing increased filling of lymphatic vessels after ligation, extending above the retroglenoid vein (RGV) level. n = 2–3/group. Data are representative of two independent experiments. Bars: (A–E and G–J) 500 µm; (F) 100 µm.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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fig2: Dura mater lymphatic vessels drain brain ISF into dcLNs. (A–J) Analysis of lymphatic outflow routes of cerebral ISF by fluorescent stereomicroscopy in Prox1-GFP (green) mice 1 h after PEG-IRDye (red) injection into the brain parenchyma without (A–F) and with (G–J) ligation of the efferent lymphatic vessel of the dcLN. See K for schematic illustration of the experimental setup and summary of the results with and without ligation. (A and B) dcLNs and scLNs (both indicated with arrowheads) showing preferential filling of the ipsilateral dcLN but no filling in the scLNs. (C) Drainage into the ipsilateral dcLN via the efferent carotid lymphatic vessels (arrowheads). CCA, common carotid artery. (D) Internal carotid artery (ICA) and adjacent lymphatic vessels (white arrowheads) immediately below the osseous skull, showing drainage from the skull (yellow arrowhead). (E and F) Lymphatic vessels around the pterygopalatine artery (PPA), showing tracer uptake by the dura mater lymphatic vessels (arrowheads) only in the basal parts of the skull, nearby their exit site. MMA, middle meningeal artery. (G) Placement of a suture around the efferent lymphatic vessel (asterisk) of the dcLN. Arrowheads, afferent lymphatic vessels. (H) Afferent lymphatic vessel of the dcLN after ligation (asterisk), showing bulging of the afferent vessels (arrowheads). (I and J) Lymphatic vessels around the posterior branch of the MMA, showing increased filling of lymphatic vessels after ligation, extending above the retroglenoid vein (RGV) level. n = 2–3/group. Data are representative of two independent experiments. Bars: (A–E and G–J) 500 µm; (F) 100 µm.
Mentions: Tracers injected into the brain ISF have been shown to translocate into the CSF via the glymphatic system and further into dcLNs (Koh et al., 2005; Iliff et al., 2012; Plog et al., 2015). However, it is unclear how these tracers gain access into the LNs. We hypothesized that the dura mater lymphatic vessels absorb brain ISF and CSF. To test this, we injected an inert 20-kD poly(ethylene glycol) (PEG) conjugate of the bright near-infrared dye IRDye 680 (PEG-IRDye; Proulx et al., 2013) into the brain parenchyma of the Prox1-GFP mice. 2 h after injection, the tracer was observed to exit the brain via paravenous routes for entry into the CSF space (not depicted), as previously reported (Iliff et al., 2012). Lymphatic drainage of brain ISF was confirmed by visualization of an intense signal in the dcLN but not in the superficial cervical LNs (scLNs; Fig. 2, A and B). Preferential drainage into the dcLN ipsilateral to the side of injection was observed (Fig. 2, A and C). When the tracer-filled afferent lymphatic vessels of the dcLNs were followed upstream, the vessels appeared to drain from the base of the skull (Fig. 2, C and D). Inside the skull, some PEG-IRDye filling of dura mater lymphatic vessels was observed only in the basal parts of the skull (Fig. 2, E and F), suggesting uptake by the lymphatic vessels but a quick washout. When the efferent lymphatic vessel of the dcLN was ligated (Fig. 2, G and H), enhanced filling of the dural lymphatic vessels was observed (Fig. 2, I–K). These data suggest that the dura mater lymphatic vessels absorb brain ISF/CSF from the subarachnoid space for transport into downstream dcLNs.

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

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.

Show MeSH
Related in: MedlinePlus