Rashbrook, Victoria Susan;
(2023)
Investigating the cellular and molecular mechanisms of postnatal neovascularisation.
Doctoral thesis (Ph.D), UCL (University College London).
Abstract
Ischemic diseases include Retinopathy of Prematurity (ROP), characterised by neovascularisation in neonatal eyes after hyperoxia, and Critical Limb Ischemia (CLI), characterised by insufficient vascularisation to the lower limb. Vascular endothelial growth factor (VEGF-A) and endothelial progenitors have been implicated as therapeutics for ischemic diseases. I investigated the role of each in mouse models of ROP and CLI, by oxygen-induced retinopathy (OIR) and induction of hindlimb ischemia (HLI) respectively. I induced OIR in mice that lacked one or both copies of Vegfa after the onset of the neovascular phase and visualised vascularisation in the retina. I found that Vegfa is required for pathological tuft formation during OIR, but not beneficial revascularisation. Each of the three major pro-angiogenic Vegfa isoforms was able to independently drive tuft formation, regardless of whether they are matrix-bound or freely secreted. These findings suggest that the VEGF-A source is local to the site of tuft formation. I induced HLI by femoral artery ligation (FAL) and monitored paw perfusion, vascularisation and VEGF-A expression in the muscle. In the ischemic gastrocnemius, I found increased VEGF-A protein 1 day after FAL, but reduced Vegfa mRNA after 4 days, despite later increases in capillarisation. These findings suggest local Vegfa upregulation may not be required for revascularisation of the ischemic gastrocnemius, and that VEGF-A protein upregulation may only be required early after FAL. I next performed FAL in mice with Csf1r-lineage tracing. We hypothesised Csf1r lineage tracing detects a novel postnatal Csf1r+ progenitor, which shares markers with developmental erythromyeloid progenitors, an endothelial cell (EC) progenitor. I observed increased Csf1r-lineage ECs in the ischemic gastrocnemius with both constitutive and temporally inducible Csf1r-lineage tracing, whereby lineage tracing was induced 1 day after FAL. These data suggest Csf1r-lineage ECs contribute to neovascularisation in the ischemic gastrocnemius, potentially through the differentiation of a circulating Csf1r+ progenitor.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Investigating the cellular and molecular mechanisms of postnatal neovascularisation |
| Language: | English |
| Additional information: | Copyright © The Author 2023. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10173111 |
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