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Title: An investigation of a possible non-neuronal cholinergic system in the vasculature
Author: Davis, Harrison E. C.
ISNI:       0000 0004 6346 614X
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2015
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Vascular endothelial cells express muscarinic acetylcholine receptors, which lead to NO- and endothelium derived hyperpolarization responses that constitute major pathways for vasodilation. As evidence suggests that perivascular nerves may not represent a viable source of innervating ACh, we investigated whether suggestions of a 'non-neuronal cholinergic system' within the vasculature might act as a source of ACh that is able to influence the endothelium. Rat mesenteric arteries were cut open and held as an en-face preparation with the endothelial cell (EC) layer exposed to measure EC [Ca2+]i. Furthermore we present the first example of EC tubes isolated from rat mesenteric arteries, used to measure EC [Ca2+]i. Immunohistochemistry was performed on intact arteries to demonstrate localization of important cholinergic proteins. Direct application of rat whole blood induced increased Ca2+ activity in ECs that did not appear to rely on shear stress or other mechanical interaction of the blood with the endothelial cells. This response, shown to rely on IP3 mediated Ca2+ release, was attenuated by the muscarinic antagonist atropine; it was concluded that blood contains or induces the release of non-neuronal ACh. The localization of the ACh synthesizing protein, choline acetyltransferase by immunohistochemistry provides evidence for a source of ACh originating within the endothelium. In accordance with this, the blocker of high affinity choline uptake, hemicholinium-3, had a significant effect in reversing choline potentiated responses in ECs. Taken together, we proposed that ACh is released potentially via organic cation transporter proteins located in the endothelium, upon stimulation by blood in response to an as yet undetermined signal. The ability to influence EC Ca2+ highlights a role for blood in the local control of these cells and the data presented suggest ACh produced locally may provide physiological relevance by exerting influence on endothelial M3 muscarinic acetylcholine receptors.
Supervisor: Garland, Christopher J. ; Dora, Kim A. Sponsor: British Heart Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available