Endothelial-specific deficiency of Junctional Adhesion Molecule-C promotes vessel normalisation in proliferative retinopathy

Thromb Haemost. 2015 Nov 25;114(6):1241-9. doi: 10.1160/TH15-01-0051. Epub 2015 Aug 27.

Abstract

In proliferative retinopathies, like proliferative diabetic retinopathy and retinopathy of prematurity (ROP), the hypoxia response is sustained by the failure of the retina to revascularise its ischaemic areas. Non-resolving retina ischaemia/hypoxia results in upregulation of pro-angiogenic factors and pathologic neovascularisation with ectopic, fragile neovessels. Promoting revascularisation of the retinal avascular area could interfere with this vicious cycle and lead to vessel normalisation. Here, we examined the function of endothelial junctional adhesion molecule-C (JAM-C) in the context of ROP. Endothelial-specific JAM-C-deficient (EC-JAM-C KO) mice and littermate JAM-C-proficient (EC-JAM-C WT) mice were subjected to the ROP model. An increase in total retinal vascularisation was found at p17 owing to endothelial JAM-C deficiency, which was the result of enhanced revascularisation and vessel normalisation, thereby leading to significantly reduced avascular area in EC-JAM-C KO mice. In contrast, pathologic neovessel formation was not affected by endothelial JAM-C deficiency. Consistent with improved vessel normalisation, tip cell formation at the interface between vascular and avascular area was higher in EC-JAM-C KO mice, as compared to their littermate controls. Consistently, JAM-C inactivation in endothelial cells resulted in increased spreading on fibronectin and enhanced sprouting in vitro in a manner dependent on β1-integrin and on the activation of the small GTPase RAP1. Together, endothelial deletion of JAM-C promoted endothelial cell sprouting, and consequently vessel normalisation and revascularisation of the hypoxic retina without altering pathologic neovascularisation. Thus, targeting endothelial JAM-C may provide a novel therapeutic strategy for promoting revascularisation and vessel normalisation in the treatment of proliferative retinopathies.

Keywords: JAM-C; angiogenesis; endothelial cells; proliferative retinopathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Adhesion
  • Cell Hypoxia
  • Cell Line
  • Cell Size
  • Cell Surface Extensions
  • Disease Models, Animal
  • Endothelial Cells
  • Endothelium, Vascular / pathology
  • Endothelium, Vascular / physiopathology*
  • Fibronectins
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Integrin beta1 / physiology
  • Ischemia / physiopathology
  • Junctional Adhesion Molecule C / deficiency*
  • Junctional Adhesion Molecule C / physiology
  • Mice
  • Mice, Knockout
  • Neovascularization, Pathologic / etiology
  • Neovascularization, Pathologic / physiopathology*
  • Organ Specificity
  • Platelet Endothelial Cell Adhesion Molecule-1 / analysis
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Retinal Vessels / physiopathology*
  • Retinal Vessels / ultrastructure
  • Retinopathy of Prematurity / physiopathology*
  • Vitreoretinopathy, Proliferative / physiopathology*
  • rap1 GTP-Binding Proteins / physiology

Substances

  • Fibronectins
  • Integrin beta1
  • Junctional Adhesion Molecule C
  • Platelet Endothelial Cell Adhesion Molecule-1
  • RNA, Small Interfering
  • rap1 GTP-Binding Proteins