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Cerebrovascular smooth muscle cells as the drivers of intramural periarterial drainage of the brain

Cerebrovascular smooth muscle cells as the drivers of intramural periarterial drainage of the brain
Cerebrovascular smooth muscle cells as the drivers of intramural periarterial drainage of the brain
The human brain is the organ with the highest metabolic activity but it lacks a traditional lymphatic system responsible for clearing waste products. We have demonstrated that the basement membranes of cerebral capillaries and arteries represent the lymphatic pathways of the brain along which intramural periarterial drainage (IPAD) of soluble metabolites occurs. Failure of IPAD could explain the vascular deposition of the amyloid-beta protein as cerebral amyloid angiopathy (CAA), which is a key pathological feature of Alzheimer’s disease. The underlying mechanisms of IPAD, including its motive force, have not been clarified, delaying successful therapies for CAA. Although arterial pulsations from the heart were initially considered to be the motive force for IPAD, they are not strong enough for efficient IPAD. This study aims to unravel the driving force for IPAD, by shifting the perspective of a heart-driven clearance of soluble metabolites from the brain to an intrinsic mechanism of cerebral arteries (e.g., vasomotion-driven IPAD). We test the hypothesis that the cerebrovascular smooth muscle cells, whose cycles of contraction and relaxation generate vasomotion, are the drivers of IPAD. A novel multiscale model of arteries, in which we treat the basement membrane as a fluid-filled poroelastic medium deformed by the contractile cerebrovascular smooth muscle cells, is used to test the hypothesis. The vasomotion-induced intramural flow rates suggest that vasomotion-driven IPAD is the only mechanism postulated to date capable of explaining the available experimental observations. The cerebrovascular smooth muscle cells could represent valuable drug targets for prevention and early interventions in CAA.
lymphatic, brain, vasomotion, Alzheimer’s disease, cerebral amyloid angiopathy, perivascular drainage, multi-scale model
1663-4365
Aldea, Roxana
f9a0de86-7ff3-4bff-abc9-b1537e14f2b8
Weller, Roy O.
4a501831-e38a-4d39-a125-d7141d6c667b
Willcock, Donna
5bf3c120-d152-4446-9078-031d964f45c4
Carare, Roxana-Octavia
0478c197-b0c1-4206-acae-54e88c8f21fa
Richardson, Giles
3fd8e08f-e615-42bb-a1ff-3346c5847b91
Aldea, Roxana
f9a0de86-7ff3-4bff-abc9-b1537e14f2b8
Weller, Roy O.
4a501831-e38a-4d39-a125-d7141d6c667b
Willcock, Donna
5bf3c120-d152-4446-9078-031d964f45c4
Carare, Roxana-Octavia
0478c197-b0c1-4206-acae-54e88c8f21fa
Richardson, Giles
3fd8e08f-e615-42bb-a1ff-3346c5847b91

Aldea, Roxana, Weller, Roy O., Willcock, Donna, Carare, Roxana-Octavia and Richardson, Giles (2019) Cerebrovascular smooth muscle cells as the drivers of intramural periarterial drainage of the brain. Frontiers in Aging Neuroscience, 11. (doi:10.3389/fnagi.2019.00001).

Record type: Article

Abstract

The human brain is the organ with the highest metabolic activity but it lacks a traditional lymphatic system responsible for clearing waste products. We have demonstrated that the basement membranes of cerebral capillaries and arteries represent the lymphatic pathways of the brain along which intramural periarterial drainage (IPAD) of soluble metabolites occurs. Failure of IPAD could explain the vascular deposition of the amyloid-beta protein as cerebral amyloid angiopathy (CAA), which is a key pathological feature of Alzheimer’s disease. The underlying mechanisms of IPAD, including its motive force, have not been clarified, delaying successful therapies for CAA. Although arterial pulsations from the heart were initially considered to be the motive force for IPAD, they are not strong enough for efficient IPAD. This study aims to unravel the driving force for IPAD, by shifting the perspective of a heart-driven clearance of soluble metabolites from the brain to an intrinsic mechanism of cerebral arteries (e.g., vasomotion-driven IPAD). We test the hypothesis that the cerebrovascular smooth muscle cells, whose cycles of contraction and relaxation generate vasomotion, are the drivers of IPAD. A novel multiscale model of arteries, in which we treat the basement membrane as a fluid-filled poroelastic medium deformed by the contractile cerebrovascular smooth muscle cells, is used to test the hypothesis. The vasomotion-induced intramural flow rates suggest that vasomotion-driven IPAD is the only mechanism postulated to date capable of explaining the available experimental observations. The cerebrovascular smooth muscle cells could represent valuable drug targets for prevention and early interventions in CAA.

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Accepted/In Press date: 7 January 2019
e-pub ahead of print date: 23 January 2019
Keywords: lymphatic, brain, vasomotion, Alzheimer’s disease, cerebral amyloid angiopathy, perivascular drainage, multi-scale model

Identifiers

Local EPrints ID: 427769
URI: https://eprints.soton.ac.uk/id/eprint/427769
ISSN: 1663-4365
PURE UUID: de6a6953-17e9-4416-9227-76715f3f0b7e

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Date deposited: 29 Jan 2019 17:30
Last modified: 14 Aug 2019 16:35

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