title: Deficient angiogenesis in redox-dead Cys17Ser PKARIα knock-in mice.
abstract: 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.
authors.affiliation: King's College London, Cardiovascular Division, The British Heart Foundation Centre of Excellence, The Rayne Institute, Saint Thomas' Hospital, London SE1 7EH, UK.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Burgoyne
authors.affiliation: King's College London, Cardiovascular Division, The British Heart Foundation Centre of Excellence, The Rayne Institute, Saint Thomas' Hospital, London SE1 7EH, UK.
authors.forename: Olena
authors.initials: O
authors.lastname: Rudyk
authors.affiliation: King's College London, Cardiovascular Division, The British Heart Foundation Centre of Excellence, The Rayne Institute, Saint Thomas' Hospital, London SE1 7EH, UK.
authors.forename: Hyun-Ju
authors.initials: HJ
authors.lastname: Cho
authors.affiliation: King's College London, Cardiovascular Division, The British Heart Foundation Centre of Excellence, The Rayne Institute, Saint Thomas' Hospital, London SE1 7EH, UK.
authors.forename: Oleksandra
authors.initials: O
authors.lastname: Prysyazhna
authors.affiliation: King's College London, Cardiovascular Division, The British Heart Foundation Centre of Excellence, The Rayne Institute, Saint Thomas' Hospital, London SE1 7EH, UK.
authors.forename: Natasha
authors.initials: N
authors.lastname: Hathaway
authors.affiliation: King's College London, Division of Imaging Sciences, The Rayne Institute, Saint Thomas' Hospital, London SE1 7EH, UK.
authors.forename: Amanda
authors.initials: A
authors.lastname: Weeks
authors.affiliation: King's College London, Division of Cancer Studies, 2nd Floor, New Hunt's House, Guy's Medical School Campus, London SE1 1UL, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Evans
authors.affiliation: King's College London, Division of Cancer Studies, 2nd Floor, New Hunt's House, Guy's Medical School Campus, London SE1 1UL, UK.
authors.forename: Tony
authors.initials: T
authors.lastname: Ng
authors.affiliation: Institut für Kardiovaskuläre Physiologie, Goethe-Universität, Theodor-Stern Kai 7, 60590 Frankfurt, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Schröder
authors.affiliation: Institut für Kardiovaskuläre Physiologie, Goethe-Universität, Theodor-Stern Kai 7, 60590 Frankfurt, Germany.
authors.forename: Ralf P
authors.initials: RP
authors.lastname: Brandes
authors.affiliation: King's College London, Cardiovascular Division, The British Heart Foundation Centre of Excellence, The James Black Centre, Denmark Hill Campus, 125 Coldharbour Lane, London SE5 9NU, UK.
authors.forename: Ajay M
authors.initials: AM
authors.lastname: Shah
authors.affiliation: King's College London, Cardiovascular Division, The British Heart Foundation Centre of Excellence, The Rayne Institute, Saint Thomas' Hospital, London SE1 7EH, UK.
authors.forename: Philip
authors.initials: P
authors.lastname: Eaton
mesh_terms: D000818:Animals; D001011:Aorta / Q000502:physiology; D002417:Cattle; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells; D005786:Gene Expression Regulation / Q000502:physiology*; D055879:Gene Knock-In Techniques; D006614:Hindlimb; D047468:Immunoprecipitation; D007511:Ischemia; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000098:blood supply; D018919:Neovascularization, Physiologic / Q000235:genetics*; D010084:Oxidation-Reduction; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
chemical_list: D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D042461:Vascular Endothelial Growth Factor A