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Vascular basement membranes as pathways for the passage of fluid into and out of the brain.

Morris AW, Sharp MM, Albargothy NJ, Fernandes R, Hawkes CA, Verma A, Weller RO, Carare RO - Acta Neuropathol. (2016)

Bottom Line: Nanoparticles did not enter capillary basement membranes from the extracellular spaces.The results of this study and previous research suggest that cerebral vascular basement membranes form the pathways by which fluid passes into and out of the brain but that different basement membrane layers are involved.The significance of these findings for neuroimmunology, Alzheimer's disease, drug delivery to the brain and the concept of the Virchow-Robin space are discussed.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Medicine, University of Southampton, Southampton General Hospital, MP806, Tremona Road, Southampton, Hampshire, SO16 6YD, UK.

ABSTRACT
In the absence of conventional lymphatics, drainage of interstitial fluid and solutes from the brain parenchyma to cervical lymph nodes is along basement membranes in the walls of cerebral capillaries and tunica media of arteries. Perivascular pathways are also involved in the entry of CSF into the brain by the convective influx/glymphatic system. The objective of this study is to differentiate the cerebral vascular basement membrane pathways by which fluid passes out of the brain from the pathway by which CSF enters the brain. Experiment 1: 0.5 µl of soluble biotinylated or fluorescent Aβ, or 1 µl 15 nm gold nanoparticles was injected into the mouse hippocampus and their distributions determined at 5 min by transmission electron microscopy. Aβ was distributed within the extracellular spaces of the hippocampus and within basement membranes of capillaries and tunica media of arteries. Nanoparticles did not enter capillary basement membranes from the extracellular spaces. Experiment 2: 2 µl of 15 nm nanoparticles were injected into mouse CSF. Within 5 min, groups of nanoparticles were present in the pial-glial basement membrane on the outer aspect of cortical arteries between the investing layer of pia mater and the glia limitans. The results of this study and previous research suggest that cerebral vascular basement membranes form the pathways by which fluid passes into and out of the brain but that different basement membrane layers are involved. The significance of these findings for neuroimmunology, Alzheimer's disease, drug delivery to the brain and the concept of the Virchow-Robin space are discussed.

No MeSH data available.


Related in: MedlinePlus

Expanded view of the wall of a cerebral artery near the surface of the cerebral cortex. a The lymphatic drainage pathway for interstitial fluid (ISF) and solutes is specifically along basement membranes surrounding smooth muscle cells in the tunica media (red arrow *). Tracer studies have shown that solutes are taken up by smooth muscle cells and by perivascular macrophages (PVM) (thin red arrows). The convective influx/glymphatic pathway by which CSF enters the brain is along the pial-glial basement membrane (BM4–green arrow **) between the layer of pia mater and the glia limitans of the brain parenchyma. Abbreviations for structure of the artery wall: Endo endothelium, BM basement membrane, SMC smooth muscle cells, GL glia limitans, BM1 basement membrane formed by the endothelium and adjacent smooth muscle cells, BM2 basement membrane formed by adjacent smooth muscle cells; this is the pathway for the lymphatic drainage of interstitial fluid and solutes from the brain along the tunica media, BM3 basement membrane formed by the outer smooth muscle cells and pia mater cells coating the artery, BM4 basement membrane formed by the pia mater and astrocytes of the glia limitans. It is along BM4 that CSF and nanoparticles enter the brain in the convective influx/glymphatic system. b Expanded view of the wall of a cerebral capillary and surrounding glia limitans. The endothelium has a basement membrane that is formed partly by endothelial cells and partly by astrocytes of the glia limitans. Solutes, such as amyloid β (Aβ) in the interstitial fluid pass from the extracellular spaces of the brain into the endothelial-glial basement membrane and drain along the intramural perivascular drainage pathway (red arrow). Tracers injected into the CSF reach the capillary basement membranes via the convective influx/glymphatic system and their entry into the interstitial fluid is dependent upon aquaporin 4 (green arrows). Nutrients from the blood through the blood–brain barrier pass into the brain through the endothelium, the basement membrane and the glia limitans (purple arrow). Pericytes are surrounded by basement membrane and lie between the endothelium (Endo) and the basement membrane (BM) of the glia limitans (GL). Although the red and green arrows are shown in separate parts of the basement membrane, a single capillary basement membrane appears to share traffic of fluid into and out of the brain
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Fig7: Expanded view of the wall of a cerebral artery near the surface of the cerebral cortex. a The lymphatic drainage pathway for interstitial fluid (ISF) and solutes is specifically along basement membranes surrounding smooth muscle cells in the tunica media (red arrow *). Tracer studies have shown that solutes are taken up by smooth muscle cells and by perivascular macrophages (PVM) (thin red arrows). The convective influx/glymphatic pathway by which CSF enters the brain is along the pial-glial basement membrane (BM4–green arrow **) between the layer of pia mater and the glia limitans of the brain parenchyma. Abbreviations for structure of the artery wall: Endo endothelium, BM basement membrane, SMC smooth muscle cells, GL glia limitans, BM1 basement membrane formed by the endothelium and adjacent smooth muscle cells, BM2 basement membrane formed by adjacent smooth muscle cells; this is the pathway for the lymphatic drainage of interstitial fluid and solutes from the brain along the tunica media, BM3 basement membrane formed by the outer smooth muscle cells and pia mater cells coating the artery, BM4 basement membrane formed by the pia mater and astrocytes of the glia limitans. It is along BM4 that CSF and nanoparticles enter the brain in the convective influx/glymphatic system. b Expanded view of the wall of a cerebral capillary and surrounding glia limitans. The endothelium has a basement membrane that is formed partly by endothelial cells and partly by astrocytes of the glia limitans. Solutes, such as amyloid β (Aβ) in the interstitial fluid pass from the extracellular spaces of the brain into the endothelial-glial basement membrane and drain along the intramural perivascular drainage pathway (red arrow). Tracers injected into the CSF reach the capillary basement membranes via the convective influx/glymphatic system and their entry into the interstitial fluid is dependent upon aquaporin 4 (green arrows). Nutrients from the blood through the blood–brain barrier pass into the brain through the endothelium, the basement membrane and the glia limitans (purple arrow). Pericytes are surrounded by basement membrane and lie between the endothelium (Endo) and the basement membrane (BM) of the glia limitans (GL). Although the red and green arrows are shown in separate parts of the basement membrane, a single capillary basement membrane appears to share traffic of fluid into and out of the brain

Mentions: The findings in this study have been combined with previous observations and summarised in Figs. 6 and 7. ISF and soluble tracers flow out of the brain along basement membranes initially in the walls of capillaries and then along basement membranes surrounding smooth muscle cells in the tunica media of arteries (shown as a continuous red line in Fig. 6). Tracers from the CSF, on the other hand, enter the brain along basement membranes on the outside of arteries between the pia mater covering of the artery and the glia limitans (Fig. 6). Previous studies have shown that when particulate tracers such as Indian ink are injected into the cisterna magna they pass into basal cisterns of the subarachnoid space and spread along narrow channels either side of major cerebral arteries over the lateral surfaces of the hemisphere [17]. From this compartment of the subarachnoid space, nanoparticles appear to pass through the pia mater on the surface of the brain to enter the pial-glial basement membranes on the outer aspects of penetrating arteries as shown in Fig. 6. A recent study demonstrated that soluble tracers penetrated the parenchyma after injection into cisterna magna, with 3 kDa tracers reaching 64 μm cortical depth [4]. The permeability characteristics of the mouse pia mater have not been fully defined and require further investigation in future studies.Fig. 6


Vascular basement membranes as pathways for the passage of fluid into and out of the brain.

Morris AW, Sharp MM, Albargothy NJ, Fernandes R, Hawkes CA, Verma A, Weller RO, Carare RO - Acta Neuropathol. (2016)

Expanded view of the wall of a cerebral artery near the surface of the cerebral cortex. a The lymphatic drainage pathway for interstitial fluid (ISF) and solutes is specifically along basement membranes surrounding smooth muscle cells in the tunica media (red arrow *). Tracer studies have shown that solutes are taken up by smooth muscle cells and by perivascular macrophages (PVM) (thin red arrows). The convective influx/glymphatic pathway by which CSF enters the brain is along the pial-glial basement membrane (BM4–green arrow **) between the layer of pia mater and the glia limitans of the brain parenchyma. Abbreviations for structure of the artery wall: Endo endothelium, BM basement membrane, SMC smooth muscle cells, GL glia limitans, BM1 basement membrane formed by the endothelium and adjacent smooth muscle cells, BM2 basement membrane formed by adjacent smooth muscle cells; this is the pathway for the lymphatic drainage of interstitial fluid and solutes from the brain along the tunica media, BM3 basement membrane formed by the outer smooth muscle cells and pia mater cells coating the artery, BM4 basement membrane formed by the pia mater and astrocytes of the glia limitans. It is along BM4 that CSF and nanoparticles enter the brain in the convective influx/glymphatic system. b Expanded view of the wall of a cerebral capillary and surrounding glia limitans. The endothelium has a basement membrane that is formed partly by endothelial cells and partly by astrocytes of the glia limitans. Solutes, such as amyloid β (Aβ) in the interstitial fluid pass from the extracellular spaces of the brain into the endothelial-glial basement membrane and drain along the intramural perivascular drainage pathway (red arrow). Tracers injected into the CSF reach the capillary basement membranes via the convective influx/glymphatic system and their entry into the interstitial fluid is dependent upon aquaporin 4 (green arrows). Nutrients from the blood through the blood–brain barrier pass into the brain through the endothelium, the basement membrane and the glia limitans (purple arrow). Pericytes are surrounded by basement membrane and lie between the endothelium (Endo) and the basement membrane (BM) of the glia limitans (GL). Although the red and green arrows are shown in separate parts of the basement membrane, a single capillary basement membrane appears to share traffic of fluid into and out of the brain
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Fig7: Expanded view of the wall of a cerebral artery near the surface of the cerebral cortex. a The lymphatic drainage pathway for interstitial fluid (ISF) and solutes is specifically along basement membranes surrounding smooth muscle cells in the tunica media (red arrow *). Tracer studies have shown that solutes are taken up by smooth muscle cells and by perivascular macrophages (PVM) (thin red arrows). The convective influx/glymphatic pathway by which CSF enters the brain is along the pial-glial basement membrane (BM4–green arrow **) between the layer of pia mater and the glia limitans of the brain parenchyma. Abbreviations for structure of the artery wall: Endo endothelium, BM basement membrane, SMC smooth muscle cells, GL glia limitans, BM1 basement membrane formed by the endothelium and adjacent smooth muscle cells, BM2 basement membrane formed by adjacent smooth muscle cells; this is the pathway for the lymphatic drainage of interstitial fluid and solutes from the brain along the tunica media, BM3 basement membrane formed by the outer smooth muscle cells and pia mater cells coating the artery, BM4 basement membrane formed by the pia mater and astrocytes of the glia limitans. It is along BM4 that CSF and nanoparticles enter the brain in the convective influx/glymphatic system. b Expanded view of the wall of a cerebral capillary and surrounding glia limitans. The endothelium has a basement membrane that is formed partly by endothelial cells and partly by astrocytes of the glia limitans. Solutes, such as amyloid β (Aβ) in the interstitial fluid pass from the extracellular spaces of the brain into the endothelial-glial basement membrane and drain along the intramural perivascular drainage pathway (red arrow). Tracers injected into the CSF reach the capillary basement membranes via the convective influx/glymphatic system and their entry into the interstitial fluid is dependent upon aquaporin 4 (green arrows). Nutrients from the blood through the blood–brain barrier pass into the brain through the endothelium, the basement membrane and the glia limitans (purple arrow). Pericytes are surrounded by basement membrane and lie between the endothelium (Endo) and the basement membrane (BM) of the glia limitans (GL). Although the red and green arrows are shown in separate parts of the basement membrane, a single capillary basement membrane appears to share traffic of fluid into and out of the brain
Mentions: The findings in this study have been combined with previous observations and summarised in Figs. 6 and 7. ISF and soluble tracers flow out of the brain along basement membranes initially in the walls of capillaries and then along basement membranes surrounding smooth muscle cells in the tunica media of arteries (shown as a continuous red line in Fig. 6). Tracers from the CSF, on the other hand, enter the brain along basement membranes on the outside of arteries between the pia mater covering of the artery and the glia limitans (Fig. 6). Previous studies have shown that when particulate tracers such as Indian ink are injected into the cisterna magna they pass into basal cisterns of the subarachnoid space and spread along narrow channels either side of major cerebral arteries over the lateral surfaces of the hemisphere [17]. From this compartment of the subarachnoid space, nanoparticles appear to pass through the pia mater on the surface of the brain to enter the pial-glial basement membranes on the outer aspects of penetrating arteries as shown in Fig. 6. A recent study demonstrated that soluble tracers penetrated the parenchyma after injection into cisterna magna, with 3 kDa tracers reaching 64 μm cortical depth [4]. The permeability characteristics of the mouse pia mater have not been fully defined and require further investigation in future studies.Fig. 6

Bottom Line: Nanoparticles did not enter capillary basement membranes from the extracellular spaces.The results of this study and previous research suggest that cerebral vascular basement membranes form the pathways by which fluid passes into and out of the brain but that different basement membrane layers are involved.The significance of these findings for neuroimmunology, Alzheimer's disease, drug delivery to the brain and the concept of the Virchow-Robin space are discussed.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Medicine, University of Southampton, Southampton General Hospital, MP806, Tremona Road, Southampton, Hampshire, SO16 6YD, UK.

ABSTRACT
In the absence of conventional lymphatics, drainage of interstitial fluid and solutes from the brain parenchyma to cervical lymph nodes is along basement membranes in the walls of cerebral capillaries and tunica media of arteries. Perivascular pathways are also involved in the entry of CSF into the brain by the convective influx/glymphatic system. The objective of this study is to differentiate the cerebral vascular basement membrane pathways by which fluid passes out of the brain from the pathway by which CSF enters the brain. Experiment 1: 0.5 µl of soluble biotinylated or fluorescent Aβ, or 1 µl 15 nm gold nanoparticles was injected into the mouse hippocampus and their distributions determined at 5 min by transmission electron microscopy. Aβ was distributed within the extracellular spaces of the hippocampus and within basement membranes of capillaries and tunica media of arteries. Nanoparticles did not enter capillary basement membranes from the extracellular spaces. Experiment 2: 2 µl of 15 nm nanoparticles were injected into mouse CSF. Within 5 min, groups of nanoparticles were present in the pial-glial basement membrane on the outer aspect of cortical arteries between the investing layer of pia mater and the glia limitans. The results of this study and previous research suggest that cerebral vascular basement membranes form the pathways by which fluid passes into and out of the brain but that different basement membrane layers are involved. The significance of these findings for neuroimmunology, Alzheimer's disease, drug delivery to the brain and the concept of the Virchow-Robin space are discussed.

No MeSH data available.


Related in: MedlinePlus