AbstractTRPAl is a member of the TRP superfamily; localised to neural and non-neuronal sites. TRPAl is activated endogenously by products of oxidative stress, where its expression on sensory neurones leads to the release of vasoactive neuropeptides. Exogenous agonists of TRPAl, mustard oil and cinnamaldehyde, have been shown to cause concentration-dependent vasorelaxation of blood vessels via a variety of mechanisms. My PhD used TRPAl WT and KO mice to investigate the potential for TRPAl to alter peripheral artery tone and the implications of this on systemic blood pressure. I also studied the development of angiotensin II induced hypertension and associated pathologies. Wire myography using murine TRPAl WT and KO mesenteric arteries showed cinnamaldehyde to cause concentration-dependent vasorelaxation comprising a TRPAl dependent component, which was endothelial independent and mediated by CGRP and hyperpolarisaton. Basal blood pressure monitoring by both tail cuff plethysmography and telemetry showed no overall effect of TRPAl deletion on basal hemodynamics. However, TRPAl KO mice displayed a previously unreported hyperactivity phenotype, measured by both telemetry and voluntary wheel running. 14 day infusion of angiotensin II by osmotic minipump induced similar hypertension in both TRPAl WT and KO mice. Hypertrophy of the heart was seen in both genotypes, but of significantly increased magnitude in TRPAl KO mice. Further analysis of associated inflammatory biomarkers by RT qPCR and MSD multiplex ELISA showed upregulation of pro-oxidative genes in hypertensive mice of both genotype. This was significantly greater in hypertensive TRPAl KO mice than in hypertensive TRPAl WT mice.
These findings may partially explain the increase in hypertrophy in these mice. Angiotensin II infused mice of both genotypes showed increases in chemokine and cytokine expression. Striking, increases in IL6 and MCP-1 seen in hypertensive WT mice were significantly blunted in hypertensive KO mice, suggesting that TRPAl may differentially modulate inflammatory responses.
|Date of Award||1 Nov 2012|
|Supervisor||Susan Brain (Supervisor) & Kalwant Authi (Supervisor)|