Differential gene expression to VEGF in aorta from wild-type and C17S PKARI knock-in mice

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 pro-angiogenic stimuli couple to NADPH oxidase-dependent generation of oxidants that catalyse an activating intermolecular-disulphide between regulatory-RI subunits of protein kinase A (PKA), which stimulates PKA-dependent ERK signalling. This is crucial to blood vessel growth as 'redox-dead' Cys17Ser RI 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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Burgoyne JR, Rudyk O, Cho HJ, Prysyazhna O, Hathaway N, Weeks A, Evans R, Ng T, Schröder K, Brandes RP, Shah AM, Eaton P