Investigating the mechanisms of CGRP-induced vasorelaxation in rat coronary arteries

Thesis

It is vital that the heart is able to match blood distribution to the metabolic demands of the myocardium. This is achieved through the modulation of coronary artery tone, with the greatest changes in vascular resistance occurring in the microvasculature. Calcitonin gene-related peptide (CGRP) is the most potent endogenous vasodilator and has been shown to have cardioprotective effects. Despite this clinical relevance, the intracellular signalling pathways underlying CGRP-induced vasorelaxation and hyperpolarization in the coronary microvasculature have not been widely studied. This thesis aimed to further elucidate these signalling pathways in isolated rat coronary septal arteries using a combination of wire and pressure myography, electrophysiology, and immunohistochemistry. Following confirmation that CGRP was indeed a potent vasorelaxant in these vessels, the present investigation determined that there is a significant endothelium-dependent component to the CGRP response which relies primarily on nitric oxide (NO) synthesis and release. Further examination revealed that CGRP activates a Gβγ subunit-mediated pathway in both the endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), rather than a Gαs subunit-mediated pathway as is widely reported in the literature. The present study is the first to study the effects of CGRP on vasorelaxation and hyperpolarization simultaneously in the coronary vasculature and demonstrated that stimulation with CGRP initiates hyperpolarization of the VSMCs. This suggests that NO acts to open EC and/or VSMC K+ channels, including KV7 channels. Finally, these investigations revealed that coronary resistance arteries do not receive sensory nerve innervation, but instead CGRP is stored in the vascular and endocardial ECs. This thesis, therefore, demonstrates that CGRP-induced vasorelaxation and hyperpolarization in the coronary microvasculature is endothelium-dependent and offers a significant, novel mechanism by which blood flow is regulated in the heart. The present findings may have clinical implications for patients with coronary microvascular dysfunction and ischaemia and, as such, warrants future research to further consolidate the intracellular signalling pathways involved.

Authors: Donovan, LA

• DOI: 10.5287/ora-eojaazem4
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: CGRP; vasorelaxation; coronary; vascular; endothelium; calcitonin gene-related peptide
• Subjects: Calcitonin gene-related peptide; Vascular resistance; Coronary arteries; Vascular endothelium; Vascular smooth muscle; Pharmacology