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Thromb Haemost 2015; 114(06): 1241-1249
DOI: 10.1160/TH15-01-0051
Endothelium and Angiogenesis
Schattauer GmbH

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

Matina Economopoulou   *
2   Department of Ophthalmology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
,
Nemanja Avramovic   *
1   Department of Clinical Pathobiochemistry, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
,
Anne Klotzsche-von Ameln
1   Department of Clinical Pathobiochemistry, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
,
Irina Korovina
1   Department of Clinical Pathobiochemistry, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
,
David Sprott
1   Department of Clinical Pathobiochemistry, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
,
Maryna Samus
1   Department of Clinical Pathobiochemistry, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
,
Bettina Gercken
1   Department of Clinical Pathobiochemistry, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
,
Maria Troullinaki
1   Department of Clinical Pathobiochemistry, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
,
Sylvia Grossklaus
1   Department of Clinical Pathobiochemistry, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
,
Richard H. Funk
3   Department of Anatomy, Medical Faculty, Technische Universität Dresden, Dresden, Germany
,
Xuri Li
4   State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, P. R. China
,
Beat A. Imhof
5   Department of Pathology and Immunology, Centre Medical Universitaire, University of Geneva, Geneva, Switzerland
,
Valeria V. Orlova
6   Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands
,
Triantafyllos Chavakis
1   Department of Clinical Pathobiochemistry, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
7   Institute for Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
› Author Affiliations
Further Information

Publication History

Received: 20 January 2015

Accepted after major revision: 09 July 2015

Publication Date:
30 November 2017 (online)

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Summary

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 proangiogenic 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 - proliferative retinopathy - angiogenesis - endothelial cells

* These authors contributed equally as first authors to the work.