Overview

This dissertation, Investigations Into the Role of Endothelial Endothelin-1 on Transient Focal Cerebral Ischemia by Wai-chung, Leung, 梁偉聰, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled Investigations into the role of endothelial endothelin-1 on transient focal cerebral ischemia Submitted by Leung Wai Chung for the degree of Doctor of Philosophy at The University of Hong Kong in December 2007 ABSTRACT Endothelin-1 (ET-1), a potent vasoconstrictor, is implicated in ischemia. Upregulation of ET-1 immunoreactivity was observed in the endothelial cells and astrocytes under hypoxia/ischemia (H/I) stress. Although the role of astrocytic ET- 1 in ischemia/reperfusion (I/R) brain injury was reported previously by our laboratory, the underlying mechanism of endothelial ET-1-mediated I/R injury remains unclear. Therefore, we made use of transgenic mice with specific ET-1 over-expression in endothelial cells by using tyrosine kinase receptor specific for endothelial cells (tie-1) promoter (TET-1) to unravel the ET-1 function on the endothelial cells. The endothelium specific increase of ET-1 in the TET-1 brain was confirmed by RT-PCR, in situ hybridization and immunohistochemistry. Although there was no gross anatomical difference on brain vasculature, vascular reactivity in response to constriction and relaxation were altered. Aorta and mesenteric arteries displayed decreased sensitivity in endothelium-dependent relaxation. In addition, aorta showed reduced smooth muscle contractile response, while mesenteric and middle cerebral artery (MCA) exhibited impaired contractile response to exogenous ET-1 application, suggesting that the chronic transgene ET- 1 over-expression leads to defect in vascular contractile responses. However, the induction of HIF-1α was not observed in TET-1 brain indicating that transgene ET-1 does not cause brain ischemia. Therefore, to further determine the role of transgene ET-1 in ischemic brain injury, the TET-1 mice were subjected to transient middle cerebral artery occlusion (MCAO). Results showed that the TET- 1 mice displayed more severe neurological score, larger infarct and higher water content in the ipsilateral hemisphere implying the deleterious role of endothelial ET-1 in I/R injury. TET-1 brain showed an augemented oxidative stress as indicated by superoxide and NADPH oxidase activation, and possibly accompanied by peroxynitrite. In addition, TET-1 ipsilateral hemisphere showed further increase in HIF-1α, VEGF and PECAM-1 compared to those of NTg mice suggesting that endothelial cells specific ET-1 over-expresssion induces the neovascularization. In line with more severe brain damage in TET-1 mice after transient MCAO, the brain injury markers such as heat shock protein 70 (HSP70) and glial fibrillary acidic protein (GFAP) expression were also further increased in TET-1 brain. These changes were accompanied by the increased ET-A receptor expression in TET-1 brain after transient MCAO. Therefore, selective and non- selective ET-receptor antagonists were applied during I/R stages to delineate the possible targets of endothelial ET-1 in ischemic stroke. The treatment of ET-A antagonist at 5 minutes after reperfusion protected TET-1 mice from cerebral infarction and improved neurological deficit, suggesting that the contribution of endothelial ET-1 on I/R brain injury is through acting on ET-A receptor. Taken together, the TET-1 model is an invaluable reagent for determining the detailed mechanism of ET-1 contribution to I/R injury. DOI:

Full Product Details

9781361420713

Table of Contents

Reviews

Author Information

Tab Content 6

Customer Reviews

Recent Reviews

Countries Available