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Title: Interactive roles of hydrogen peroxide and calcium in the endothelial signaling network that underpins the EDHF phenomenon
Author: Li, Yiwen
ISNI:       0000 0004 2734 775X
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2012
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Endothelium-derived hydrogen peroxide (H2O2) has been suggested to function as a freely diffusible endothelium derived hyperpolarizing factor (EDHF). However, in the rabbit vasculature, it has been shown that the electrotonic spread of endothelial hyperpolarization via myoendothelial and homocellular smooth muscle gap junctions is essential for nitric oxide (NO)-prostanoid-independent arterial relaxation. Therefore, a series of interlinked experiments, both mechanical and imaging, have been undertaken to investigate the role of H2O2 in vascular control, focusing on the mechanisms through which H2O2 may regulate intracellular endothelial calcium (Ca2+) homeostasis. These studies have shown that exogenous H2O2 does not directly mediate an EDHF-type response, but can potentiate electrotonically-mediated relaxations by facilitating the elevation of endothelial cell intracellular Ca2+ concentration ([Ca2+]i), thereby promoting the activation of hyperpolarizing endothelial Ca2+-activated potassium channels (KCa). Mechanistically, this potentiating effect of H2O2 involves enhanced depletion of the ryanodine-sensitive endoplasmic reticulum Ca2+ store, through inhibition of sarcoplasmic-endoplasmic reticulum Ca2+-ATPase (SERCA) activity, and therefore increased extracellular Ca2+ influx through store-operated Ca2+ entry. This effect of H2O2 is independent of the nature of the initiating stimulus, as it is observed with both the receptor-coupled agonist acetylcholine and the SERCA pump inhibitor cyclopiazonic acid. Paradoxically, however, H2O2 was also shown to exert inhibitory effects on NO-mediated endothelium-dependent relaxations. Additionally, arsenite was found to modulate vascular responses through the elevation of the endogenous endothelial-produced H2O2 that is secondary to the activation of NADPH oxidase. This thesis provides evidence that H2O2 is a physiological-important signalling molecule in endothelial Ca2+ homeostasis. The findings also give further insights into the mechanism underlying the compensatory role of the EDHF phenomenon to compromised NO-mediated response that are observed in diseased vessels.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: R Medicine (General)