Reversal of endothelial dysfunction reduces white matter vulnerability in cerebral small vessel disease in rats

Rajani, R. M. et al. (2018) Reversal of endothelial dysfunction reduces white matter vulnerability in cerebral small vessel disease in rats. Science Translational Medicine, 10(448), eaam9507. (doi:10.1126/scitranslmed.aam9507) (PMID:29973407)

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Abstract

Dementia is a major social and economic problem for our aging population. One of the most common of dementia in the elderly is cerebral small vessel disease (SVD). Magnetic resonance scans of SVD patients typically show white matter abnormalities, but we do not understand the mechanistic pathological link between blood vessels and white matter myelin damage. Hypertension is suggested as the cause of sporadic SVD, but a recent alternative hypothesis invokes dysfunction of the blood-brain barrier as the primary cause. In a rat model of SVD, we show that endothelial cell (EC) dysfunction is the first change in development of the disease. Dysfunctional ECs secrete heat shock protein 90α, which blocks oligodendroglial differentiation, contributing to impaired myelination. Treatment with EC-stabilizing drugs reversed these EC and oligodendroglial pathologies in the rat model. EC and oligodendroglial dysfunction were also observed in humans with early, asymptomatic SVD pathology. We identified a loss-of-function mutation in ATPase11B, which caused the EC dysfunction in the rat SVD model, and a single-nucleotide polymorphism in ATPase11B that was associated with white matter abnormalities in humans with SVD. We show that EC dysfunction is a cause of SVD white matter vulnerability and provide a therapeutic strategy to treat and reverse SVD in the rat model, which may also be of relevance to human SVD.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Dominiczak, Professor Anna and Graham, Dr Delyth
Authors: Rajani, R. M., Quick, S., Ruigrok, S. R., Graham, D., Harris, S. E., Verhaaren, B. F.J., Fornage, M., Seshadri, S., Atanur, S. S., Dominiczak, A. F., Smith, C., Wardlaw, J. M., and Williams, A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Science Translational Medicine
Publisher:American Association for the Advancement of Science
ISSN:1946-6234
ISSN (Online):1946-6242
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in Science Translational Medicine 10(448): eaam9507
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
617771BHF centre of excellenceRhian TouyzBritish Heart Foundation (BHF)RE/13/5/30177RI CARDIOVASCULAR & MEDICAL SCIENCES