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Molecular and cellular studies of the role of urokinase plasminogen activator in cutaneous wound healing

Daniel, Richard James; (2003) Molecular and cellular studies of the role of urokinase plasminogen activator in cutaneous wound healing. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Re-epithelialization is a pivotal process in normal skin repair. Studies from knockout mice demonstrate that an intact plasminogen activator system is an essential requirement for this process and thus for wound healing. In this study, transgenic mice were generated overexpressing urokinase plasminogen activator (uPA) to assess the effect on cutaneous wound healing. Constitutive epidermal overexpression resulted in embryonic toxicity. However, mice generated with uPA under the inducible control of the Cre/LoxP system or K6 promoter (K6-uPAtg) facilitated effective uPA induction. Importantly, analysis of K6-uPAtg mice demonstrated a marked induction of functional uPA upon cutaneous wounding. Subsequent wounding analyses, however, showed no gross differences from wild-type wounds, suggesting that complex regulation of uPA occurs within cutaneous wounds. A key consequence of cutaneous wounding is the development of tissue hypoxia, a potent stimulus for increased keratinocyte migration and hence re- epithelialization. As the mechanisms responsible for this remain unclear, the relationship between hypoxia, plasminogen activation and in vitro wound healing was assessed. Exposure of keratinocytes to hypoxia resulted in upregulation of uPA and uPAR mRNA and an increase in functional uPA. Addition of a serine protease inhibitor or selective uPA inhibitors, significantly reduced keratinocyte motility in hypoxic cultures and abrogated the hypoxic enhancement of in vitro wound closure. These data indicate a central role for uPA in hypoxic keratinocyte migration and suggest a mechanism for enhanced re-epithelialization of wounds under low oxygen tensions. An important inhibitor of uPA, PAI-I, is also implicated in wound-related cellular migration. The effect of hypoxia on keratinocyte PAI-I expression was therefore evaluated. Exposure to hypoxia resulted in upregulation of PAI-1 mRNA and protein. Antibody-mediated neutralisation of VEGF partially inhibited this hypoxic induction, suggesting that VEGF stimulates PAI-I in hypoxic keratinocytes. The subsequent detection of VEGF receptor mRNA in keratinocytes indicated a potential signalling pathway for this VEGF-mediated stimulation.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Molecular and cellular studies of the role of urokinase plasminogen activator in cutaneous wound healing
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences; Wound healing
URI: https://discovery.ucl.ac.uk/id/eprint/10102517
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