Medical Biology - Theses
Permanent URI for this collection
Search Results
1 - 1 of 1
-
ItemThe role of BCL2 family proteins in apoptosis regulation during angiogenesis( 2016)Blood vessels are multicellular tubes, lined with endothelial cells (ECs), that form a hierarchical network essential for the distribution of blood, oxygen, nutrients, hormones and immune cells around the body and removal of metabolic waste products from tissues. Angiogenesis, the growth of new vessels from pre-existing ones, is essential to match the size of the blood vessel network to the metabolic demands of growing tissues. During this process, an over-production of vessels results in the formation of a dense vessel plexus that is inefficient for blood flow. From this dense network, excess vessels undergo a process of selective regression termed ‘pruning’ to produce a mature, hierarchical vessel network. EC apoptosis occurs as part of the angiogenic remodelling processes, but its contribution to angiogenic vessel remodelling, be it vessel pruning or some other purpose, has remained unclear. In this thesis I directly investigated the role of EC apoptosis during angiogenesis by analysing mice in which ECs were unable to execute the apoptotic program regulated by BCL2 family proteins. I found that while EC apoptosis improved the efficiency of selective vessel pruning, it was ultimately dispensable for this process. Instead, blood vessels formed in the absence of EC apoptosis contained excessive numbers of ECs resulting in increased diameter of mature capillaries. Having established that the BCL2 family was essential for promoting EC death during angiogenesis, I investigated whether pro-survival members of the family were required for the survival of ECs during angiogenesis. Using the neonatal retina as a model for angiogenesis, I found that while BCL2 was not required for EC survival during angiogenic vessel growth (Chapter 4), MCL1 was required in a dose-dependent manner (Chapter 5). In contrast to normal angiogenesis, BCL2 and MCL1 were both independently required for the growth of abnormal vascular lesions in a murine model of pathological retina angiogenesis (Chapter 6). These studies have conclusively determined the role for EC apoptosis during angiogenic growth and remodelling and provide evidence that targeting distinct BCL2 family pro-survival proteins may be a useful therapeutic approach for targeting pathological angiogenesis.