The deep and periventricular white matter is preferentially affected in several neurological disorders, including cerebral small vessel disease (SVD) and multiple sclerosis (MS), suggesting that common pathogenic mechanisms may be involved in this injury. Here we consider the potential pathogenic role of tissue hypoxia in lesion development, arising partly from the vascular anatomy of the affected white matter. Specifically, these regions are supplied by a sparse vasculature fed by long, narrow end arteries/arterioles that are vulnerable to oxygen desaturation if perfusion is reduced (as in SVD, MS and diabetes) or if the surrounding tissue is hypoxic (as in MS, at least). The oxygen crisis is exacerbated by a local preponderance of veins, as these can become highly desaturated ‘sinks’ for oxygen that deplete it from surrounding tissues. Additional haemodynamic deficiencies, including sluggish flow and impaired vasomotor reactivity and vessel compliance, further exacerbate oxygen insufficiency. The cells most vulnerable to hypoxic damage, including oligodendrocytes, die first, resulting in demyelination. Indeed, in preclinical models, demyelination is prevented if adequate oxygenation is maintained by raising inspired oxygen concentrations. In agreement with this interpretation, there is a predilection of lesions for the anterior and occipital horns of the lateral ventricles, namely regions located at arterial watersheds, or border zones, known to be especially susceptible to hypoperfusion and hypoxia. Finally, mitochondrial dysfunction due to genetic causes, as occurs in leucodystrophies or due to free radical damage, as occurs in MS, will compound any energy insufficiency resulting from hypoxia. Viewing lesion formation from the standpoint of tissue oxygenation not only reveals that lesion distribution is partly predictable, but may also inform new therapeutic strategies.
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October 2017
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In this issue of Clinical Science, Thompson et al (pages 2489-2501) describe their research on the capacity of protein tyrosine phosphatase 1B inhibitor to reverse atherosclerotic plaque formation in a mouse model. The cover image shows aortic root sections of mice fed on a high-fat-diet that are stained with Oil Red - a method the authors used to quantify plaque formation in this study.
Review Article|
October 13 2017
Understanding a role for hypoxia in lesion formation and location in the deep and periventricular white matter in small vessel disease and multiple sclerosis
Santiago Martinez Sosa;
Santiago Martinez Sosa
1Department of Neuroinflammation and Queen Square MS Centre, UCL Institute of Neurology, Queen Square, London WC1N 3BG, U.K.
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Kenneth J. Smith
1Department of Neuroinflammation and Queen Square MS Centre, UCL Institute of Neurology, Queen Square, London WC1N 3BG, U.K.
Correspondence: Kenneth J. Smith ([email protected])
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Publisher: Portland Press Ltd
Received:
April 16 2017
Revision Received:
August 01 2017
Accepted:
August 15 2017
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2017
Clin Sci (Lond) (2017) 131 (20): 2503–2524.
Article history
Received:
April 16 2017
Revision Received:
August 01 2017
Accepted:
August 15 2017
Citation
Santiago Martinez Sosa, Kenneth J. Smith; Understanding a role for hypoxia in lesion formation and location in the deep and periventricular white matter in small vessel disease and multiple sclerosis. Clin Sci (Lond) 1 October 2017; 131 (20): 2503–2524. doi: https://doi.org/10.1042/CS20170981
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