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Title: The effects of cerebral ischaemia on pericytes and neurovascular function
Author: Neuhaus, Ain
ISNI:       0000 0004 6494 019X
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2016
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Acute ischaemic stroke is a major cause of morbidity and mortality in the developed world, yet the treatment options available are limited to therapies that restore vessel patency. Recanalisation of the occluded artery does not necessarily result in reperfusion of the downstream microvasculature, however, and the pathomechanisms involved in this are incompletely understood. One putative mediator of this is the capillary pericyte, a vascular mural cell type that may constrict under ischaemic conditions. The overarching aim of this thesis was to characterise vascular function following cerebral ischaemia, using in vivo, ex vivo and in vitro approaches. First, I demonstrated that ischaemia reduced both ipsilateral and contralateral cerebral blood flow responses to hypercapnia, and diminished reactivity of isolated pressurised arteries. I then developed a novel assay to characterise human pericyte contractility in vitro, and demonstrated that they are responsive to vasoactive substances even in the absence of αSMA expression. In this assay, chemical ischaemia caused pericyte contraction and subsequent death, consistent with in vivo reports describing their role in the no-reflow phenomenon. Finally, I explored whether the voltage-gated Ca2+ channel antagonist nimodipine could improve reperfusion in cerebral ischaemia, and found that rats treated with nimodipine exhibited improved post-ischaemic cerebral blood flow and ameliorated neurological impairment. However, I did not find a direct effect of nimodipine on pericyte contractility during chemical ischaemia in vitro, indicating that nimodipine may be targeting other cell types in the vasculature. Together, these data highlight the importance of vascular function following stroke and shed light on putative vasculoprotective approaches, which have translational potential to improve reperfusion in patients receiving recanalisation therapy.
Supervisor: Buchan, Alastair ; Anthony, Daniel Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available