INVESTIGATING THE MOLECULAR REGULATION OF ANGIOGENESIS IN THE HEART
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Angiogenesis is the formation of new blood vessels from pre-existing ones, and is an essential process during tissue regeneration, growth, reproduction and development. It is a highly regulated event that involves the interplay of multiple different signalling networks, and if dysregulated, can contribute to several different pathological conditions, including arthritis, diabetic retinopathy, heart disease and cancer. The signalling networks that mediate angiogenesis consist of a complex balance between many stimulatory or inhibitory factors. Those same key factors can regulate the proliferation, migration and remodelling of endothelial cells that form the basis of an organised vasculature. Thus, the regulation of angiogenesis is a common thread between seemingly unrelated diseases, like heart disease and cancer. My PhD acts as a bridge between the molecular regulation of cardiac and cancer blood vessels – learning from the latter to apply to cardiac disease. Herein we have investigated two questions: (1) The utility of low dose Cilengitide in the treatment of heart failure. (2) The role of endothelial cell focal adhesion kinase and angiocrine signalling in cancer. We demonstrate that treatment with low dose Cilengitide reduces or even reverses the pathogenesis of heart failure within a murine model of pressure-overload induced heart failure. We go on to show that low dose Cilengitide enhances myocardial angiogenesis and may also beneficially target the cardiomyocyte itself directly. Furthermore, we show that targeting the kinase domain of focal adhesion kinase within the endothelium is crucial for tumour cell sensitisation to the DNA-damaging therapy, doxorubicin.
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