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Title: The importance of endoglin for cardiac structure and function
Authors: Davison, Benjamin John
Issue Date: 2014
Publisher: Newcastle University
Abstract: Endoglin is an accessory receptor for the transforming growth factor beta family. Patients carrying mutations in the endoglin gene develop the inherited vascular dysplasia, Hereditary Haemorrhagic Telangiectasia (HHT). However, it is becoming apparent that endoglin may also be important in acquired cardiovascular diseases such as hypertension, atherosclerosis and heart failure. The work in this thesis investigates the role of endoglin in the structure and function of the adult cardiovascular system by utilising a conditional endoglin knockout model and murine cardiac magnetic resonance imaging (CMR). I established and validated murine CMR at Newcastle University allowing accurate quantification of in vivo cardiac structure and function in a number of mouse models of cardiac disease either at single time points or in longitudinal studies. Immunohistochemical analysis confirmed that endoglin is expressed in the endocardium and vasculature of the adult mouse heart. Following myocardial infarction there was increased endoglin expression which co-localised with endothelial cells and myofibroblasts. Cre-lox genetics was then used to ubiquitously knockdown endoglin in the adult mouse. This resulted in significant ventricular remodelling within three weeks, with ventricular dilatation associated with cardiomyocyte hypertrophy. These changes gradually progressed over three months following endoglin knockdown; however, overt heart failure was not seen within this time frame. Invasive measurement of ventricular function suggested an impairment of vasomotor control and reduced contractile reserve following endoglin knockdown. Also, using an endothelial-specific endoglin knockdown mouse I demonstrated that these novel cardiac changes were due to endoglin depletion in endothelial cells. Together these data suggests that the alterations in cardiac structure and function are secondary to alterations in the wider cardiovascular system. This is supported by evidence of eNOS uncoupling following endoglin knockdown. The results reported in this thesis describe a novel phenotype and highlight the importance of endoglin in the maintenance of cardiac structure and function. Further work will clarify the mechanism behind these alterations.
Description: PhD Thesis
Appears in Collections:Institute of Genetic Medicine

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