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

Cardiovasc Res. 2015 Sep 1;107(4):478-86. doi: 10.1093/cvr/cvv186. Epub 2015 Jun 30.

Abstract

Aims: 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.

Methods and 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.

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 ischaemic heart disease.

Keywords: Myocardial ischaemia; Oedema; Rip2; VEGFR2; Vascular permeability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Capillary Permeability / physiology
  • Cells, Cultured
  • Coronary Artery Disease / metabolism
  • Endothelial Cells / metabolism*
  • Humans
  • Mice
  • Myocardial Ischemia / metabolism*
  • Myocardial Reperfusion Injury / metabolism
  • Myocardium / metabolism*
  • Receptor-Interacting Protein Serine-Threonine Kinase 2 / metabolism*
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Vascular Endothelial Growth Factor A
  • RIPK2 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinase 2
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk2 protein, mouse