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Beta-adrenoceptor modulation of dermal endothelial cell function and angiogenesis

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posted on 2013-03-06, 09:50 authored by Andrew Philip O'Leary
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.

History

Supervisor(s)

Pullar, Chistine

Date of award

2013-01-01

Awarding institution

University of Leicester

Qualification level

  • Doctoral

Qualification name

  • PhD

Language

en

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