Investigation into ion channel- and nitric oxide-mediated vasodilation in resistance arteries
<p>Effective regulation of resistance artery tone is essential in maintaining adequate tissue perfusion across the body. Artery tone is determined by various ion channels, with voltage-gated calcium channels (VGCCs) expressed by vascular smooth muscle cells (VSMCs) being key in facilitating th...
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| Format: | Thesis |
| Language: | English |
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2024
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| _version_ | 1824459059491766272 |
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| author | Wallis, LE |
| author2 | Dora, K |
| author_facet | Dora, K Wallis, LE |
| author_sort | Wallis, LE |
| collection | OXFORD |
| description | <p>Effective regulation of resistance artery tone is essential in maintaining adequate tissue perfusion across the body. Artery tone is determined by various ion channels, with voltage-gated calcium channels (VGCCs) expressed by vascular smooth muscle cells (VSMCs) being key in facilitating the influx of Ca<sup>2+</sup> required for vasoconstriction. The endothelium provides the main vasodilatory signals, including nitric oxide (NO) and endothelium-derived hyperpolarisation (EDH).</p>
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<p>The first part of this study develops a protocol to detect basal and stimulated NO release in intact, <em>ex vivo</em> resistance arteries using a fluorescent dye. For the first time, this will allow real-time NO release to be monitored in physiologically relevant artery preparations, addressing an important gap in vascular research.</p>
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<p>The second part of this study investigates the function and expression of T-type VGCCs in rat mesenteric and coronary arteries. While the role of L-type VGCCs has been long established in larger arteries, recent research has highlighted the importance of T-type VGCCs in smaller resistance arteries and their potential involvement in vasodilation. Using RNAscope and immunohistochemistry, we confirm the presence of Ca<sub>V</sub>3.1, Ca<sub>V</sub>3.2, and Ca<sub>V</sub>3.3 channels in endothelial cells (ECs) and VSMCs. Functional studies indicate that these channels contribute to vasodilation through smooth muscle-mediated signalling, particularly by interacting with BK<sub>Ca</sub> channels. For the first time in myogenically-active coronary arteries, we show that blocking Ca<sub>V</sub>3.2 channels produces vasoconstriction, revealing their paradoxical role in opposing contraction and maintaining vascular tone. Furthermore, we show the expression of T-type VGCCs by VSMCs at the points where myoendothelial projections (MEPs) make contact, raising the possibility that these channels contribute to myoendothelial feedback vasodilation.</p>
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<p>The final part of this study explores the expression of hyperpolarisation-activated cyclic nucleotide-gated (HCN) channels by ECs of resistance arteries. We provide the first evidence that HCN channels are present in the endothelium, which corresponds to unpublished functional data from the Dora/Garland group demonstrating their role in facilitating Ca<sup>2+</sup> influx in hyperpolarised cells.</p>
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<p>Overall, these findings enhance our understanding of microvascular function and provide a basis for further research which may have significant clinical implications.</p> |
| first_indexed | 2025-02-19T04:35:46Z |
| format | Thesis |
| id | oxford-uuid:0c551fab-61c7-4950-920a-3eeac80889bc |
| institution | University of Oxford |
| language | English |
| last_indexed | 2025-02-19T04:35:46Z |
| publishDate | 2024 |
| record_format | dspace |
| spelling | oxford-uuid:0c551fab-61c7-4950-920a-3eeac80889bc2025-02-03T11:36:20ZInvestigation into ion channel- and nitric oxide-mediated vasodilation in resistance arteriesThesishttp://purl.org/coar/resource_type/c_db06uuid:0c551fab-61c7-4950-920a-3eeac80889bcPharmacologyEnglishHyrax Deposit2024Wallis, LEDora, KGarland, C<p>Effective regulation of resistance artery tone is essential in maintaining adequate tissue perfusion across the body. Artery tone is determined by various ion channels, with voltage-gated calcium channels (VGCCs) expressed by vascular smooth muscle cells (VSMCs) being key in facilitating the influx of Ca<sup>2+</sup> required for vasoconstriction. The endothelium provides the main vasodilatory signals, including nitric oxide (NO) and endothelium-derived hyperpolarisation (EDH).</p> <br> <p>The first part of this study develops a protocol to detect basal and stimulated NO release in intact, <em>ex vivo</em> resistance arteries using a fluorescent dye. For the first time, this will allow real-time NO release to be monitored in physiologically relevant artery preparations, addressing an important gap in vascular research.</p> <br> <p>The second part of this study investigates the function and expression of T-type VGCCs in rat mesenteric and coronary arteries. While the role of L-type VGCCs has been long established in larger arteries, recent research has highlighted the importance of T-type VGCCs in smaller resistance arteries and their potential involvement in vasodilation. Using RNAscope and immunohistochemistry, we confirm the presence of Ca<sub>V</sub>3.1, Ca<sub>V</sub>3.2, and Ca<sub>V</sub>3.3 channels in endothelial cells (ECs) and VSMCs. Functional studies indicate that these channels contribute to vasodilation through smooth muscle-mediated signalling, particularly by interacting with BK<sub>Ca</sub> channels. For the first time in myogenically-active coronary arteries, we show that blocking Ca<sub>V</sub>3.2 channels produces vasoconstriction, revealing their paradoxical role in opposing contraction and maintaining vascular tone. Furthermore, we show the expression of T-type VGCCs by VSMCs at the points where myoendothelial projections (MEPs) make contact, raising the possibility that these channels contribute to myoendothelial feedback vasodilation.</p> <br> <p>The final part of this study explores the expression of hyperpolarisation-activated cyclic nucleotide-gated (HCN) channels by ECs of resistance arteries. We provide the first evidence that HCN channels are present in the endothelium, which corresponds to unpublished functional data from the Dora/Garland group demonstrating their role in facilitating Ca<sup>2+</sup> influx in hyperpolarised cells.</p> <br> <p>Overall, these findings enhance our understanding of microvascular function and provide a basis for further research which may have significant clinical implications.</p> |
| spellingShingle | Pharmacology Wallis, LE Investigation into ion channel- and nitric oxide-mediated vasodilation in resistance arteries |
| title | Investigation into ion channel- and nitric oxide-mediated vasodilation in resistance arteries |
| title_full | Investigation into ion channel- and nitric oxide-mediated vasodilation in resistance arteries |
| title_fullStr | Investigation into ion channel- and nitric oxide-mediated vasodilation in resistance arteries |
| title_full_unstemmed | Investigation into ion channel- and nitric oxide-mediated vasodilation in resistance arteries |
| title_short | Investigation into ion channel- and nitric oxide-mediated vasodilation in resistance arteries |
| title_sort | investigation into ion channel and nitric oxide mediated vasodilation in resistance arteries |
| topic | Pharmacology |
| work_keys_str_mv | AT wallisle investigationintoionchannelandnitricoxidemediatedvasodilationinresistancearteries |