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Title: Beta-adrenoceptor modulation of dermal endothelial cell function and angiogenesis
Author: O'Leary, Andrew Philip
ISNI:       0000 0004 2733 4879
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2013
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Angiogenesis is an essential process in wound healing. An insufficient angiogenic response can result in chronic wounds, whilst an overzealous response can contribute to scarring and cancer metastasis. Beta-adrenoceptors (β-AR) are G protein-coupled receptors (GPCR) and have previously been shown to play a role in wound healing, however their role in angiogenesis, is currently unknown. It was hypothesised that β-AR activation or blockade will reduce and promote human dermal microvascular endothelial cell (HDMEC) angiogenic functions and angiogenesis. β-AR activation was both anti-motogenic and anti-mitogenic. In addition, protein kinase A and exchange proteins directly activated by cAMP (EPAC) played a role in modulating the β-AR-mediated decrease in migration rate. Meanwhile, immunoprecipitation studies revealed that both the β1-AR and β2-AR co-localised with EPAC. Finally, inhibiting cyclic adenosine monophosphate (cAMP) signalling pathways reduced proliferation. Perhaps a decrease in cAMP underpinned the β-AR-mediated decrease in proliferation rate. In more complex environments, β-AR activation both promoted and delayed, whilst β-AR blockade promoted tubule formation. Meanwhile, β-AR activation and blockade both increased and reduced aortic outgrowth. In the chick chorio-allantoic membrane assay, β-AR activation and blockade both reduced and increase angiogenesis. Finally, enzyme linked-immunosorbent assays demonstrated that β-AR modulation altered vascular endothelial growth factor A secretion from human neonatal keratinocytes and fibroblast growth factor 2 secretion from HDMECs and human dermal fibroblasts. In conclusion, activating or inhibiting β-ARs can modulate HDMEC function and angiogenesis in vitro, ex vivo and in vivo. Therefore, the use of β-AR agonists and antagonists could be promising modulators of angiogenesis.
Supervisor: Pullar, Chistine Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available