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dc.contributor.advisorHadoke, Patrick
dc.contributor.advisorBradley, Mark
dc.contributor.advisorDhaliwal, Kanwaldeep
dc.contributor.authorStott, Holly Rosannah
dc.date.accessioned2017-10-05T10:02:19Z
dc.date.available2017-10-05T10:02:19Z
dc.date.issued2017-07-08
dc.identifier.urihttp://hdl.handle.net/1842/23609
dc.description.abstractMatrix metalloproteinases (MMPs) are required for tissue remodelling processes, including angiogenesis. MMP activity is generally proangiogenic but MMP-12 is suggested to be antiangiogenic and its precise role is still unclear. The work in this thesis describes the synthesis of an MMP-12 inhibitor and activity probe to address the hypothesis that MMP-12 inhibits angiogenesis. An inhibitor, synthesised in-house, selectively inhibited MMP-12 in in vitro recombinant enzyme assays. An activity probe, also synthesised in-house, was selective for MMP-12 in in vitro recombinant enzyme assays. The function of MMP-12 during angiogenesis was assessed using murine models of angiogenesis; the in vivo sponge implantation, and the ex vivo aortic ring assays. Angiogenesis and MMP activity were imaged in vivo in sponges in C57Bl6/J mice over 7 − 21 days (D) using commercial probes (MMPSense™ and AngioSense™). MMP-12 protein concentration and activity were higher in sponges during early angiogenesis (D 3 − 7) when gene expression of vascular endothelial growth factor (a proangiogenic marker) was also high. Gene expression for MMP-12 and platelet-derived growth factor receptor (a marker of vascular maturation) were both higher on D 21 as angiogenesis started to stabilise. The MMP-12 activity probe was unsuccessful in selectively detecting MMP-12 activity in sponge lysate mixtures from D 7 − 21. Administration of an MMP-12 inhibitor did not increase angiogenesis in the sponges in vivo. Additionally, sponges implanted in MMP-12-/- mice did not exhibit significant changes in angiogenesis or MMP activity when imaged in vivo using commercial probes (MMPSense™ and AngioSense™) on D 7. Supporting this, histological analysis of the sponges (removed on D 21) showed that deletion of MMP-12 also did not increase angiogenesis within the sponges.en
dc.contributor.sponsorotheren
dc.language.isoenen
dc.publisherThe University of Edinburghen
dc.subjectmatrix metalloproteinasesen
dc.subjectMMPsen
dc.subjectMMP-12 inhibitoren
dc.subjectangiogenesisen
dc.titleMMP-12 activity during vascular remodellingen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen


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