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Title: Dynamic regulation of endothelial P2X7 receptors by blood flow patterns associated with atherosclerosis
Author: Green, Jack P.
ISNI:       0000 0004 6347 7586
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2016
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Aims: Atherosclerosis occurs predominantly at arterial branches and bends that are exposed to disturbed patterns of blood flow. These sites show augmented endothelial inflammatory signalling. Endothelial cells release ATP in response to acute high shear stress but the role of ATP during chronic exposure to low oscillatory shear stress (atheroprone flow) has not been investigated. ATP signalling has been demonstrated to regulate pro-inflammatory signalling. This present study proposes that ATP signalling is enhanced at sites of atheroprone flow and aims to investigate this in endothelial cells subjected to shear stress patterns associated with atherosclerosis and atheroprotection. Methods and Results: Human umbilical vein endothelial cells (HUVEC) were cultured under physiological atheroprotective or atheroprone flow for 72 hours and endothelial ATP-mediated responses were measured using live cell calcium imaging. Atheroprone flow-conditioned HUVEC exhibited an enhanced ATP-mediated calcium response, which was dependent on calcium influx from the extracellular space through the ATPgated P2X7 ion channels. Endothelial P2X7 receptor expression was enhanced in vitro under atheroprone flow conditions and in vivo at atherosusceptible sites of the murine aorta. Furthermore, the ATPase CD39 was up-regulated under atheroprotective flow and this enhanced CD39 activity regulated ATP-induced calcium responses. P2X7 inhibitors were used to evaluate the role of P2X7 under atheroprone flow. P2X7 activation mediated the induction of pro-atherosclerotic interleukin-8 and E-selectin due to disturbed flow. EMP2 was identified as a regulator of macrophage P2X7 responses and its expression was enhanced in endothelial cells under atheroprotective flow patterns, suggesting further regulatory mechanisms of P2X7 signalling may occur in the endothelium. Conclusion: P2X7 receptors are selectively activated in endothelial cells under atheroprone flow and contribute to the endothelial dysfunction associated with atherogenesis at arterial sites of disturbed flow.
Supervisor: Wilson, Heather L. ; Evans, Paul C. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available