Blood vessels form an extensive network that pervades the vertebrate body to deliver oxygen and nutrients. This network develops during the early steps of embryogenesis by two processes termed vasculogenesis and angiogenesis. Blood vessels and neurons share several guidance cues and cell surface receptors that control their behaviour during embryogenesis. These proteins have been named angioneurins. The transmembrane protein neuropilin 1 (NRP1) is an angioneurin and interacts with various structurally diverse molecules, including the semaphorin SEMA3A, the VEGF164 isoform of vascular endothelial growth factor, the cell-adhesion molecule L1 and heparan sulfate proteoglycans (HSPGs). In the mouse, targeted-disruption of Nrp1 leads to a wide spectrum of cardiovascular and neuronal defects, resulting in embryonic lethality. Brain vascularisation is severely affected in Nrp1-null embryos, and it has been hypothesised that this is due to impaired VEGF164 signalling in the absence of NRP1. In this thesis, it is shown that vascular defects in Nrp1^{-/-} embryos are only partially phenocopied by loss of VEGF164, suggesting that NRP1 interacts with additional proteins to control vessel development. To test this possibility, the contribution of SEMA3A, L1 and HSPGs to angiogenesis was assessed. Microvessel branching in the hindbrain and limb development in mouse embryos deficient in these candidate molecules were studied to compare the relative contribution of these molecules to neuronal versus vascular patterning. In these model systems, NRP1 contributed to neurovascular patterning by preferentially relaying SEMA3A signals in peripheral axon and VEGF164 signals in endothelial cells. Whilst L1 was not required for brain angiogenesis, HSPGs played an essential role most likely by controlling VEGF distribution in the extracellular matrix. Unexpectedly, the hindbrain model revealed that NRP1 plays a dual role during brain vascularisation by functioning not only in the endothelium, but also in macrophages. These findings provide new insights into the NRP1-mediated mechanism controlling vessel patterning.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:505251 |
| Date | January 2008 |
| Creators | Vieira, Joaquim Miguel |
| 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/17233/ |
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