published_or_final_version / Pharmacology / Master / Master of Philosophy

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The mechanisms by which Angiopoietin-1 (Ang-1) modulates the survival of human endothelial cells were investigated. Ang-1 inhibited both TNFalpha-induced and serum deprivation-evoked apoptosis, an effect which was associated with attenuation of caspase activation, inhibition of Smac release from the mitochondria, up-regulation of Survivin-1 expression (IAPs member) and a significant activation of the pro-survival PI-3 kinase/AKT pathway. In addition, Ang-1 activated, in a time-dependent fashion, both the anti-apoptotic ERK1/2 and pro-apoptotic p38 MAP kinases. Ang-1-evoked ERK1/2 activation was mediated in part through the PI-3 kinase pathway, whereas both, the PI-3 kinase and ERK1/2 attenuated p38 MAP kinase activation. / We conclude that Ang-1 promotes endothelial cell survival through several pathways including the PI-3 kinase/AKT and ERK1/2 pathways, up-regulation of Survivin-1 as well as inhibition of Smac release and caspase activity. The preferential activation of these anti-apoptotic effects, as opposed to the activation of pro-apoptotic p38 MAP kinase, results in a net survival response.

Angiogenesis is an essential physiological process involved in wound repair, endometrial growth and embryogenesis and is tightly regulated in normal tissues. However, angiogenesis is also associated with some pathological conditions; in these conditions, angiogenesis eludes regulation and presents as either unabated (as in diabetic retinopathy and neoplasia), or as an inefficient process (as in ischaemic coronary disease). Regardless of this, all angiogenic mechanisms have a common biological basis, ergo, the shift of anti-angiogenic research has been towards biologically-based angiogenesis inhibitors; it is well established that these anti-angiogenic paradigms can be applied to inhibit the growth of solid neoplasms. / Antagonists of tumour-associated angiogenesis from a diverse range of sources have been identified and analysed, including agents capable of eliciting an apoptotic response in the endothelial cells lining the tumour vasculature. Tumour-associated microvascular endothelial cells, although derived from normal, host endothelial cells, exhibit differential characteristics which are able to be exploited, in order to induce endothelial cell apoptosis in tumour vessels, while normal, host vessels remain unaffected. / Thesis (PhDBiomedicalScience)--University of South Australia, 2005.

Angiogenesis is an essential physiological process involved in wound repair, endometrial growth and embryogenesis and is tightly regulated in normal tissues. However, angiogenesis is also associated with some pathological conditions; in these conditions, angiogenesis eludes regulation and presents as either unabated (as in diabetic retinopathy and neoplasia), or as an inefficient process (as in ischaemic coronary disease). Regardless of this, all angiogenic mechanisms have a common biological basis, ergo, the shift of anti-angiogenic research has been towards biologically-based angiogenesis inhibitors; it is well established that these anti-angiogenic paradigms can be applied to inhibit the growth of solid neoplasms. / Antagonists of tumour-associated angiogenesis from a diverse range of sources have been identified and analysed, including agents capable of eliciting an apoptotic response in the endothelial cells lining the tumour vasculature. Tumour-associated microvascular endothelial cells, although derived from normal, host endothelial cells, exhibit differential characteristics which are able to be exploited, in order to induce endothelial cell apoptosis in tumour vessels, while normal, host vessels remain unaffected. / Thesis (PhDBiomedicalScience)--University of South Australia, 2005.

Thesis (M.S.)--Auburn University, 2007. / Abstract. Vita. Includes bibliographic references (ℓ. 37-44)

Thesis (M. Phil.)--University of Hong Kong, 2008. / Also available in print.

Diss. (sammanfattning) Uppsala : Univ., 2003. / Härtill 5 uppsatser.