Yang, Zhiyuan; (2023) Investigating the roles of vascular dysfunction and tissue hypoxia in the pathogenesis of multiple sclerosis and cerebral small vessel disease – a route for therapy? Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Multiple sclerosis (MS) is an inflammatory and degenerative disease of the CNS. Recently, tissue hypoxia, caused by vascular dysfunction, has been identified as an important factor in MS, leading to demyelination and neurological deficits. Cerebral small vessel disease (cSVD) describes pathologies in the small vessels of the brain. It has been suggested that MS and cSVD share considerable similarities, including evidence of pathogenic haemodynamic deficiencies. Furthermore, an excessive burden of vascular pathology, likely caused by ageing, has been proposed as a potential contributor to neurodegeneration in progressive MS. However, a clear understanding of how vascular dysfunction contributes to the diseases has not yet been fully revealed, impeding development of potential treatments. Here, we aim to use animal disease models to study the role of vascular dysfunction in the pathogenesis of MS and cSVD. We also aim to investigate the potentially beneficial effects on vascular and neurological function of therapies that promote blood flow and increase tissue oxygenation, and to explore underlying mechanisms using (immuno)histological methods. Three animal models were used, namely experimental autoimmune encephalomyelitis (EAE, a common model of MS), the spontaneously hypertensive stroke-prone rat (SHRSP, a common model of cSVD), and a novel rat model of post-inflammatory slow-burning neurodegeneration. We examined 1) neurological function including visual evoked potentials, neurological deficits and cognitive function; 2) in vivo vascular function including blood flow, neurovascular coupling and cerebral vascular reactivity; and 3) pathology using (immuno)histological methods. We provide physiological, functional, histological and therapeutic evidence that vascular dysfunction is, in part, responsible for neurological deficits, neurodegeneration and cognitive decline in the respective animal models. We therefore conclude that the vascular dysfunction occurring in MS and cSVD is likely to be an important factor in causing neurological deficits, neurodegeneration and cognitive decline. Furthermore, protecting vascular function and tissue oxygenation is expected to provide significant clinical benefit.

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