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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.

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.

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Terminally differentiated lymphatic vessels in the dura mater of the brain. Visualization of CNS lymphatic vasculature using Prox1-GFP reporter mice with DiI counterstaining for blood vasculature, Vegfr3+/LacZ reporter mice and immunofluorescence for PECAM1, and the lymphatic markers PROX1, LYVE1, PDPN, CCL21, and VEGFR3, as indicated. White arrowheads denote lymphatic vessels, yellow arrowheads denote the skull exit sites, and asterisks denote valves. (A) A schematic image of the various areas analyzed. The letters in bold refer to the corresponding images below. MMA, middle meningeal artery; PPA, pterygopalatine artery; RGV, retroglenoid vein; RRV, rostral rhinal vein; SS, sigmoid sinus; SSS, superior sagittal sinus; TV, transverse vein. (B) Lymphatic vessels running down along the SS and exiting the skull. (C) Lymphatic vessels running down along the proximal MMA branches. (D) Lymphatic vessels around the RGV with some vessels exiting the skull. (E–H) Whole-mount LYVE1 immunofluorescence of the skull top and base. (E) Lymphatic vessels along the SSS and the distal parts of the anterior MMA branch extending toward the bregma. (F) Lymphatic vessels along the SSS, bifurcating into the TVs at the confluence of sinuses. (G) Lymphatic vessels exiting the skull along the optic (II) and the trigeminal (V) nerves and through the cribriform plate (CP). CN, cranial nerve. (H) Lymphatic vessels associated with the glossopharyngeal (IX), vagus (X), and accessory (XI) nerves. XII, hypoglossal nerve. (I and J) Stereomicrographs of tissues in a Vegfr3+/LacZ reporter mouse showing the skull exit of dural lymphatic vessels along the PPA (I) and through the CP into a nasal concha. OB, olfactory bulb area. (K) Immunofluorescence of thick skull section for PECAM1, PROX1, and CCL21. bv, blood vessel; sas, subarachnoid space. (L–P) Whole-mount immunofluorescence staining of superior sagittal lymphatic vessels with antibodies against PECAM1 (L), LYVE1 (M), PDPN (N), CCL21 (O), VEGFR3 (P), and PROX1 (M–P). LYVE1 and PECAM1 colocalization is indicated with the dashed lines. n = 2–3 per staining. Data are from two to three independent experiments. Bars: (B–H and L–P) 100 µm; (K) 50 µm.
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fig1: Terminally differentiated lymphatic vessels in the dura mater of the brain. Visualization of CNS lymphatic vasculature using Prox1-GFP reporter mice with DiI counterstaining for blood vasculature, Vegfr3+/LacZ reporter mice and immunofluorescence for PECAM1, and the lymphatic markers PROX1, LYVE1, PDPN, CCL21, and VEGFR3, as indicated. White arrowheads denote lymphatic vessels, yellow arrowheads denote the skull exit sites, and asterisks denote valves. (A) A schematic image of the various areas analyzed. The letters in bold refer to the corresponding images below. MMA, middle meningeal artery; PPA, pterygopalatine artery; RGV, retroglenoid vein; RRV, rostral rhinal vein; SS, sigmoid sinus; SSS, superior sagittal sinus; TV, transverse vein. (B) Lymphatic vessels running down along the SS and exiting the skull. (C) Lymphatic vessels running down along the proximal MMA branches. (D) Lymphatic vessels around the RGV with some vessels exiting the skull. (E–H) Whole-mount LYVE1 immunofluorescence of the skull top and base. (E) Lymphatic vessels along the SSS and the distal parts of the anterior MMA branch extending toward the bregma. (F) Lymphatic vessels along the SSS, bifurcating into the TVs at the confluence of sinuses. (G) Lymphatic vessels exiting the skull along the optic (II) and the trigeminal (V) nerves and through the cribriform plate (CP). CN, cranial nerve. (H) Lymphatic vessels associated with the glossopharyngeal (IX), vagus (X), and accessory (XI) nerves. XII, hypoglossal nerve. (I and J) Stereomicrographs of tissues in a Vegfr3+/LacZ reporter mouse showing the skull exit of dural lymphatic vessels along the PPA (I) and through the CP into a nasal concha. OB, olfactory bulb area. (K) Immunofluorescence of thick skull section for PECAM1, PROX1, and CCL21. bv, blood vessel; sas, subarachnoid space. (L–P) Whole-mount immunofluorescence staining of superior sagittal lymphatic vessels with antibodies against PECAM1 (L), LYVE1 (M), PDPN (N), CCL21 (O), VEGFR3 (P), and PROX1 (M–P). LYVE1 and PECAM1 colocalization is indicated with the dashed lines. n = 2–3 per staining. Data are from two to three independent experiments. Bars: (B–H and L–P) 100 µm; (K) 50 µm.

Mentions: After removing the brain from the skull, no lymphatic vessels were seen on the brain parenchyma or pia mater (not depicted). However, a surprisingly extensive network of lymphatic vessels was observed in the meninges underlying the skull bones (Fig. 1, A–J; and Video 1). In sagittal planes of the inner skull, lymphatic vessels were observed to run down toward the base of the skull along the transverse sinus, the sigmoid sinus, the retroglenoid vein, the rostral rhinal vein, and the major branches of the middle and anterior meningeal arteries (Fig. 1, B and D; and Video 1). In preparations of the superior portions of the skull, the lymphatic vessels were visualized along the superior sagittal sinus, the transverse sinus, the rostral rhinal veins, and the middle meningeal artery (Fig. 1, E and F). A concentration of lymphatic vessels could be observed to exit the skull along the meningeal portions of the pterygopalatine artery, a branch of the internal carotid artery which dives in and out of the skull to give rise to the middle meningeal artery (Fig. 1 I). Lymphatic vessels along the sigmoid sinus and retroglenoid vein exited the skull along the veins (Fig. 1, B and D). In preparations of the base of the skull, lymphatic vessels could be seen in the distal portion of several cranial nerves (optic, trigeminal, glossopharyngeal, vagus, and accessory), exiting the skull along the nerve (Fig. 1, G and H). Lymphatic vessels could be observed also in the dural lining of the cribriform plate, where some vessels passed through the skull into the nasal mucosa (Fig. 1, G and J).


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)

Terminally differentiated lymphatic vessels in the dura mater of the brain. Visualization of CNS lymphatic vasculature using Prox1-GFP reporter mice with DiI counterstaining for blood vasculature, Vegfr3+/LacZ reporter mice and immunofluorescence for PECAM1, and the lymphatic markers PROX1, LYVE1, PDPN, CCL21, and VEGFR3, as indicated. White arrowheads denote lymphatic vessels, yellow arrowheads denote the skull exit sites, and asterisks denote valves. (A) A schematic image of the various areas analyzed. The letters in bold refer to the corresponding images below. MMA, middle meningeal artery; PPA, pterygopalatine artery; RGV, retroglenoid vein; RRV, rostral rhinal vein; SS, sigmoid sinus; SSS, superior sagittal sinus; TV, transverse vein. (B) Lymphatic vessels running down along the SS and exiting the skull. (C) Lymphatic vessels running down along the proximal MMA branches. (D) Lymphatic vessels around the RGV with some vessels exiting the skull. (E–H) Whole-mount LYVE1 immunofluorescence of the skull top and base. (E) Lymphatic vessels along the SSS and the distal parts of the anterior MMA branch extending toward the bregma. (F) Lymphatic vessels along the SSS, bifurcating into the TVs at the confluence of sinuses. (G) Lymphatic vessels exiting the skull along the optic (II) and the trigeminal (V) nerves and through the cribriform plate (CP). CN, cranial nerve. (H) Lymphatic vessels associated with the glossopharyngeal (IX), vagus (X), and accessory (XI) nerves. XII, hypoglossal nerve. (I and J) Stereomicrographs of tissues in a Vegfr3+/LacZ reporter mouse showing the skull exit of dural lymphatic vessels along the PPA (I) and through the CP into a nasal concha. OB, olfactory bulb area. (K) Immunofluorescence of thick skull section for PECAM1, PROX1, and CCL21. bv, blood vessel; sas, subarachnoid space. (L–P) Whole-mount immunofluorescence staining of superior sagittal lymphatic vessels with antibodies against PECAM1 (L), LYVE1 (M), PDPN (N), CCL21 (O), VEGFR3 (P), and PROX1 (M–P). LYVE1 and PECAM1 colocalization is indicated with the dashed lines. n = 2–3 per staining. Data are from two to three independent experiments. Bars: (B–H and L–P) 100 µm; (K) 50 µm.
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fig1: Terminally differentiated lymphatic vessels in the dura mater of the brain. Visualization of CNS lymphatic vasculature using Prox1-GFP reporter mice with DiI counterstaining for blood vasculature, Vegfr3+/LacZ reporter mice and immunofluorescence for PECAM1, and the lymphatic markers PROX1, LYVE1, PDPN, CCL21, and VEGFR3, as indicated. White arrowheads denote lymphatic vessels, yellow arrowheads denote the skull exit sites, and asterisks denote valves. (A) A schematic image of the various areas analyzed. The letters in bold refer to the corresponding images below. MMA, middle meningeal artery; PPA, pterygopalatine artery; RGV, retroglenoid vein; RRV, rostral rhinal vein; SS, sigmoid sinus; SSS, superior sagittal sinus; TV, transverse vein. (B) Lymphatic vessels running down along the SS and exiting the skull. (C) Lymphatic vessels running down along the proximal MMA branches. (D) Lymphatic vessels around the RGV with some vessels exiting the skull. (E–H) Whole-mount LYVE1 immunofluorescence of the skull top and base. (E) Lymphatic vessels along the SSS and the distal parts of the anterior MMA branch extending toward the bregma. (F) Lymphatic vessels along the SSS, bifurcating into the TVs at the confluence of sinuses. (G) Lymphatic vessels exiting the skull along the optic (II) and the trigeminal (V) nerves and through the cribriform plate (CP). CN, cranial nerve. (H) Lymphatic vessels associated with the glossopharyngeal (IX), vagus (X), and accessory (XI) nerves. XII, hypoglossal nerve. (I and J) Stereomicrographs of tissues in a Vegfr3+/LacZ reporter mouse showing the skull exit of dural lymphatic vessels along the PPA (I) and through the CP into a nasal concha. OB, olfactory bulb area. (K) Immunofluorescence of thick skull section for PECAM1, PROX1, and CCL21. bv, blood vessel; sas, subarachnoid space. (L–P) Whole-mount immunofluorescence staining of superior sagittal lymphatic vessels with antibodies against PECAM1 (L), LYVE1 (M), PDPN (N), CCL21 (O), VEGFR3 (P), and PROX1 (M–P). LYVE1 and PECAM1 colocalization is indicated with the dashed lines. n = 2–3 per staining. Data are from two to three independent experiments. Bars: (B–H and L–P) 100 µm; (K) 50 µm.
Mentions: After removing the brain from the skull, no lymphatic vessels were seen on the brain parenchyma or pia mater (not depicted). However, a surprisingly extensive network of lymphatic vessels was observed in the meninges underlying the skull bones (Fig. 1, A–J; and Video 1). In sagittal planes of the inner skull, lymphatic vessels were observed to run down toward the base of the skull along the transverse sinus, the sigmoid sinus, the retroglenoid vein, the rostral rhinal vein, and the major branches of the middle and anterior meningeal arteries (Fig. 1, B and D; and Video 1). In preparations of the superior portions of the skull, the lymphatic vessels were visualized along the superior sagittal sinus, the transverse sinus, the rostral rhinal veins, and the middle meningeal artery (Fig. 1, E and F). A concentration of lymphatic vessels could be observed to exit the skull along the meningeal portions of the pterygopalatine artery, a branch of the internal carotid artery which dives in and out of the skull to give rise to the middle meningeal artery (Fig. 1 I). Lymphatic vessels along the sigmoid sinus and retroglenoid vein exited the skull along the veins (Fig. 1, B and D). In preparations of the base of the skull, lymphatic vessels could be seen in the distal portion of several cranial nerves (optic, trigeminal, glossopharyngeal, vagus, and accessory), exiting the skull along the nerve (Fig. 1, G and H). Lymphatic vessels could be observed also in the dural lining of the cribriform plate, where some vessels passed through the skull into the nasal mucosa (Fig. 1, G and J).

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