Cerebrovascular Smooth Muscle Cells as the Drivers of Intramural Periarterial Drainage of the Brain.

Roxana Aldea,Giles Richardson,Roxana O Carare,Donna M Wilcock,Roy O Weller

doi:10.3389/fnagi.2019.00001

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.

Highlights

The brain lacks a conventional lymphatic system, which in the rest of the body is responsible for removing waste products and excess fluid (Aspelund et al, 2015; Louveau et al, 2015; Bakker et al, 2016)
We propose that the forces generated by cerebral vascular smooth muscle cells (VSMCs) can drive intramural periarterial drainage (IPAD) in the brain by acting upon the deformable basement membranes (BMs)
Since the motive force for IPAD has remained unresolved (Diem et al, 2017), we have proposed and tested with in silico modeling the idea of vasomotion-driven IPAD

Summary

Introduction

The brain lacks a conventional lymphatic system, which in the rest of the body is responsible for removing waste products and excess fluid (Aspelund et al, 2015; Louveau et al, 2015; Bakker et al, 2016). Inefficient removal of Aβ from the brain leads to parenchymal amyloid plaques and cerebral amyloid angiopathy (CAA), commonly seen in the Vasomotion-Driven Periarterial Drainage commonest form of dementia, Alzheimer’s disease (AD) (Selkoe, 2001; Ross and Poirier, 2005; Cupino and Zabel, 2014). Aging highly increases the risk for CAA and dementia and, considering increased longevity, the occurrence of dementia by 2050 is evaluated to 131 million people (Prince et al, 2016). This increases the urgency to explore potential unconventional clearance mechanisms for Aβ that may contribute toward maintaining the homeostasis of the brain (Tarasoff-Conway et al, 2015; Bakker et al, 2016)

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