Rip2 modifies VEGF-induced signalling and vascular permeability in myocardial ischaemia

Linda Andersson, Margareta Scharin Täng, Annika Lundqvist, Malin Lindbom, Ismena Mardani, Per Fogelstrand, Puja Shahrouki, Björn Redfors, Elmir Omerovic, Max Levin, Jan Borén, Malin C. Levin
Cardiovascular Research2015
Aims In myocardial ischaemia, vascular endothelial growth factor (VEGF) induces permeability by activating a signalling path- way 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 sig- nalling and myocardial ischaemia/reperfusion injury. Methods To determine whether Rip2 has a role in VEGF signalling, we used cultured endothelial cells in which Rip2 was or was and results 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 re- sulted in enhanced vascular permeability, increased oedema and expanding area of myocardial damage, and markedly reduced heart function after long-term follow-up. Conclusion 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 ischae- mic heart disease.

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