Angiogenesis is the sprouting of new capillaries from pre-existing vessels and is driven by hypoxia. While physiological hypoxia in the retina is paramount to regulating physiological angiogenesis, pathological ischemia is a cause of pathological neovascularisation and a large proportion of blindness worldwide. The aim of this thesis is to explore ways of redirecting neovascularisation towards healthy revascularisation. I do this by looking at ways of modulating angiogenesis at an early stage in Oxygen-induced retinopathy (OIR) in mice. This model is based on vessel depletion by exposure to hyperoxia, which results in acute retinal hypoxia upon return to room air. This hypoxia then triggers neovascularisation in the remaining vessels after 5 days. Vascular endothelial growth factor (Vegf) plays a critical role in development and disease of the retinal vasculature. Genetic ablation of astrocyte-derived Vegf surprisingly showed minor impacts on retinal vasculature development. However, it had a vessel stabilizing role during the hyperoxic phase and also promoted vessel regeneration in the hypoxic phase. In other experiments, it was shown that C3H/HeJ mice, which contain the retinal degeneration 1 (Rd1) mutation (Pde6bRd1) and have abnormally thin retinas, do not become ischemic despite vaso-obliteration and do not develop neovascularisation. This demonstrates that maintaining a balance between oxygen demand and supply at the onset of ischemia critically influences the angiogenesis outcome. Using this model, vascular tortuosity was established as an early phenotype of OIR possibly predictive of neovascularisation. Finally, in other experiments, it was shown that inflammation can modulate hypoxia. Subcutaneous injection of lipopolysaccharide (LPS) in mice with hypoxic retinas, led to bilateral reduction of hypoxia, reduction of VEGF and healthy revascularization. From a conceptual point of view, this is a paradigm changer because it shows for the first time that it is possible to change hypoxia in the retina without changing the oxygen (i.e. vascular) supply.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:626589 |
| Date | January 2014 |
| Creators | Scott, A. |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1427875/ |
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