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Deficient angiogenesis in redox-dead Cys17Ser PKARIα knock-in mice
Joseph R Burgoyne1, Olena Rudyk1, Hyun-Ju Cho1
1King's College London, Cardiovascular Division, The British Heart Foundation Centre of Excellence, The Rayne Institute, Saint Thomas' Hospital, London SE1 7EH, UK.
None:
Angiogenesis is essential for tissue development, wound healing and tissue perfusion, with its dysregulation linked to tumorigenesis, rheumatoid arthritis and heart disease. Here we show that pro-angiogenic stimuli couple to NADPH oxidase-dependent generation of oxidants that catalyse an activating intermolecular-disulphide between regulatory-RIα subunits of protein kinase A (PKA), which stimulates PKA-dependent ERK signalling. This is crucial to blood vessel growth as 'redox-dead' Cys17Ser RIα knock-in mice fully resistant to PKA disulphide-activation have deficient angiogenesis in models of hind limb ischaemia and tumour-implant growth. Disulphide-activation of PKA represents a new therapeutic target in diseases with aberrant angiogenesis.
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