title: Rip2 modifies VEGF-induced signalling and vascular permeability in myocardial ischaemia.
abstract: OBJECTIVE
  In myocardial ischaemia, vascular endothelial growth factor (VEGF) induces permeability by activating a signalling pathway that includes VEGF receptor 2 (VEGFR2), resulting in increased oedema and inflammation and thereby expanding the area of tissue damage. In this study, we investigated the role of receptor-interacting protein 2 (Rip2) in VEGF signalling and myocardial ischaemia/reperfusion injury.
  
  
  RESULTS
  To determine whether Rip2 has a role in VEGF signalling, we used cultured endothelial cells in which Rip2 was or was not inactivated. In Rip2-deficient endothelial cells, stimulation with VEGF resulted in more rapid kinetics of VEGFR2 phosphorylation than in control cells. Rip2 deficiency also enhanced VEGF-induced activation of ERK1/2, suggesting an increased propensity for endothelial permeability. In a mouse model of myocardial ischaemia, Rip2 deficiency resulted in enhanced vascular permeability, increased oedema and expanding area of myocardial damage, and markedly reduced heart function after long-term follow-up.
  
  
  CONCLUSIONS
  Our results show that Rip2 modifies VEGF-induced signalling and vascular permeability in myocardial ischaemia. These findings indicate that Rip2 may be a promising novel therapeutic target to reduce excess vascular permeability in ischaemic heart disease.
authors.affiliation: Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, 413 45 Göteborg, Sweden.
authors.forename: Linda
authors.initials: L
authors.lastname: Andersson
authors.affiliation: Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, 413 45 Göteborg, Sweden.
authors.forename: Margareta
authors.initials: M
authors.lastname: Scharin Täng
authors.affiliation: Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, 413 45 Göteborg, Sweden.
authors.forename: Annika
authors.initials: A
authors.lastname: Lundqvist
authors.affiliation: Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, 413 45 Göteborg, Sweden.
authors.forename: Malin
authors.initials: M
authors.lastname: Lindbom
authors.affiliation: Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, 413 45 Göteborg, Sweden.
authors.forename: Ismena
authors.initials: I
authors.lastname: Mardani
authors.affiliation: Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, 413 45 Göteborg, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Fogelstrand
authors.affiliation: Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, 413 45 Göteborg, Sweden.
authors.forename: Puja
authors.initials: P
authors.lastname: Shahrouki
authors.affiliation: Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, 413 45 Göteborg, Sweden.
authors.forename: Björn
authors.initials: B
authors.lastname: Redfors
authors.affiliation: Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, 413 45 Göteborg, Sweden.
authors.forename: Elmir
authors.initials: E
authors.lastname: Omerovic
authors.affiliation: Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, 413 45 Göteborg, Sweden.
authors.forename: Max
authors.initials: M
authors.lastname: Levin
authors.affiliation: Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, 413 45 Göteborg, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Borén
authors.affiliation: Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, 413 45 Göteborg, Sweden malin.levin@wlab.gu.se.
authors.forename: Malin C
authors.initials: MC
authors.lastname: Levin
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000502:physiology; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D006801:Humans; D051379:Mice; D017202:Myocardial Ischemia / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2 / Q000378:metabolism*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D042461:Vascular Endothelial Growth Factor A; C506253:RIPK2 protein, human; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506255:Ripk2 protein, mouse
keywords: Myocardial ischaemia; Oedema; Rip2; VEGFR2; Vascular permeability