Novel mechanisms in angiogenesis and vascular permeability.
Doctoral thesis, UCL (University College London).
Vascular networks expand in a two-step process that begins with vessel sprouting followed by vessel anastomosis. Sprouting is induced by chemotactic gradients of the vascular endothelial growth factor (VEGF), which stimulates tip cell protrusion. Yet, it is not known which factors promote the fusion of neighbouring tip cells to add new circuits to the vessel network. In this thesis, the role of macrophages in physiological angiogenesis was examined. By combining the analysis of mouse mutants defective in macrophage development or VEGF signalling with live-imaging in zebrafish, I demonstrated that macrophages promote tip cell fusion downstream of VEGF-mediated tip cell induction. Macrophages therefore play a hitherto unidentified role as vascular fusion cells. Moreover, I showed that there are striking molecular similarities between the pro-angiogenic tissue macrophages essential for vascular development and those that promote the angiogenic switch in cancer, including the expression of the cell-surface proteins TIE2 and NRP1. These findings suggest that tissue macrophages are a target for anti-angiogenic therapies, but that they could equally well be exploited to stimulate tissue vascularisation in ischemic disease. The VEGF non-tyrosine kinase receptor neuropilin 1 (NRP1) is essential for vascular development. NRP1 has been previously hypothetised to transduce signals through its cytoplasmic domain to promote angiogenesis independently of the VEGF tyrosine kinase receptors. However, by studying a new mouse mutant for NRP1 I found that the NRP1 cytoplasmic domain did not play any obvious role in cardiovascular development or neo-angiogenesis in a model of CNV. In contrast, I found that loss of the NRP1 cytoplasmic domain confers resistance to VEGF-induced vascular permeability. These findings implicate the NRP1 cytoplasmic domain as a key molecular switch between VEGF-induced angiogenesis and vascular hyperpermeability, making it an ideal pharmacological target in ischemic diseases where oedema caused by leaky vessels exacerbates disease progression.
|Title:||Novel mechanisms in angiogenesis and vascular permeability|
|Additional information:||Permission for digitisation not received|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology|
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