Biomaterial Database

Reversal of endothelial dysfunction reduces white matter vulnerability in cerebral small vessel disease in rats. 2018

Rikesh M Rajani, and Sophie Quick, and Silvie R Ruigrok, and Delyth Graham, and Sarah E Harris, and Benjamin F J Verhaaren, and Myriam Fornage, and Sudha Seshadri, and Santosh S Atanur, and Anna F Dominiczak, and Colin Smith, and Joanna M Wardlaw, and Anna Williams

Medical Research Council (MRC) Centre for Regenerative Medicine and UK Dementia Research Institute, University of Edinburgh, Edinburgh EH16 4UU, UK.

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.

UI	MeSH Term	Description	Entries
D006973	Hypertension	Persistently high systemic arterial BLOOD PRESSURE. Based on multiple readings (BLOOD PRESSURE DETERMINATION), hypertension is currently defined as when SYSTOLIC PRESSURE is consistently greater than 140 mm Hg or when DIASTOLIC PRESSURE is consistently 90 mm Hg or more.	Blood Pressure, High,Blood Pressures, High,High Blood Pressure,High Blood Pressures
D008875	Middle Aged	An adult aged 45 - 64 years.	Middle Age
D001812	Blood-Brain Barrier	Specialized non-fenestrated tightly-joined ENDOTHELIAL CELLS with TIGHT JUNCTIONS that form a transport barrier for certain substances between the cerebral capillaries and the BRAIN tissue.	Brain-Blood Barrier,Hemato-Encephalic Barrier,Barrier, Blood-Brain,Barrier, Brain-Blood,Barrier, Hemato-Encephalic,Barriers, Blood-Brain,Barriers, Brain-Blood,Barriers, Hemato-Encephalic,Blood Brain Barrier,Blood-Brain Barriers,Brain Blood Barrier,Brain-Blood Barriers,Hemato Encephalic Barrier,Hemato-Encephalic Barriers
D004195	Disease Models, Animal	Naturally-occurring or experimentally-induced animal diseases with pathological processes analogous to human diseases.	Animal Disease Model,Animal Disease Models,Disease Model, Animal
D004730	Endothelium, Vascular	Single pavement layer of cells which line the luminal surface of the entire vascular system and regulate the transport of macromolecules and blood components.	Capillary Endothelium,Vascular Endothelium,Capillary Endotheliums,Endothelium, Capillary,Endotheliums, Capillary,Endotheliums, Vascular,Vascular Endotheliums
D006720	Homozygote	An individual in which both alleles at a given locus are identical.	Homozygotes
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000073637	Oligodendrocyte Precursor Cells	Neuroglial cells that first appear during mid-embryogenesis in the central nervous system of mammals and give rise to OLIGODENDROCYTES. Mitotically-active populations remain through late adulthood and are capable of regenerating MYELIN lost to disease or injury.	Oligodendrocyte Precursors,Oligodendrocyte Progenitor Cells,Oligodendrocyte Progenitors,Pre-Oligodendrocytes,Preoligodendrocytes,Cell, Oligodendrocyte Precursor,Cell, Oligodendrocyte Progenitor,Cells, Oligodendrocyte Precursor,Cells, Oligodendrocyte Progenitor,Oligodendrocyte Precursor,Oligodendrocyte Precursor Cell,Oligodendrocyte Progenitor,Oligodendrocyte Progenitor Cell,Pre Oligodendrocytes,Pre-Oligodendrocyte,Precursor Cell, Oligodendrocyte,Precursor Cells, Oligodendrocyte,Precursor, Oligodendrocyte,Precursors, Oligodendrocyte,Preoligodendrocyte,Progenitor Cell, Oligodendrocyte,Progenitor Cells, Oligodendrocyte,Progenitor, Oligodendrocyte,Progenitors, Oligodendrocyte
D000251	Adenosine Triphosphatases	A group of enzymes which catalyze the hydrolysis of ATP. The hydrolysis reaction is usually coupled with another function such as transporting Ca(2+) across a membrane. These enzymes may be dependent on Ca(2+), Mg(2+), anions, H+, or DNA.	ATPases,Adenosinetriphosphatase,ATPase,ATPase, DNA-Dependent,Adenosine Triphosphatase,DNA-Dependent ATPase,DNA-Dependent Adenosinetriphosphatases,ATPase, DNA Dependent,Adenosinetriphosphatases, DNA-Dependent,DNA Dependent ATPase,DNA Dependent Adenosinetriphosphatases,Triphosphatase, Adenosine
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia