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Thromb Haemost 2019; 119(03): 439-448
DOI: 10.1055/s-0038-1676966
Endothelium and Angiogenesis
Georg Thieme Verlag KG Stuttgart · New York

53BP1 Deficiency Promotes Pathological Neovascularization in Proliferative Retinopathy

Maria Troullinaki
1   Institute of Clinical Chemistry and Laboratory Medicine, University Clinic Carl Gustav Carus, TU Dresden, Dresden, Germany
,
Ruben Garcia-Martin
1   Institute of Clinical Chemistry and Laboratory Medicine, University Clinic Carl Gustav Carus, TU Dresden, Dresden, Germany
,
David Sprott
1   Institute of Clinical Chemistry and Laboratory Medicine, University Clinic Carl Gustav Carus, TU Dresden, Dresden, Germany
,
Anne Klotzsche-von Ameln
2   Institute of Physiology, Faculty of Medicine, TU Dresden, Dresden, Germany
,
Sylvia Grossklaus
1   Institute of Clinical Chemistry and Laboratory Medicine, University Clinic Carl Gustav Carus, TU Dresden, Dresden, Germany
,
Ioannis Mitroulis
1   Institute of Clinical Chemistry and Laboratory Medicine, University Clinic Carl Gustav Carus, TU Dresden, Dresden, Germany
,
Triantafyllos Chavakis
1   Institute of Clinical Chemistry and Laboratory Medicine, University Clinic Carl Gustav Carus, TU Dresden, Dresden, Germany
,
Matina Economopoulou
3   Department of Ophthalmology, University Clinic Carl Gustav Carus, TU Dresden, Dresden, Germany
4   DFG Research Centre and Cluster of Excellence for Regenerative Therapies Dresden, TU Dresden, Dresden, Germany
› Author Affiliations Funding This work was supported by the Else-Kröner-Fresenius Stiftung.
Further Information

Publication History

07 June 2018

19 November 2018

Publication Date:
08 January 2019 (online)

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Abstract

The replication stress inflicted on retinal endothelial cells (ECs) in the context of hypoxia-induced pathological neovascularization during proliferative retinopathy is linked with activation of the deoxyribonucleic acid (DNA) repair response. Here, we studied the effect of deficiency of the DNA damage response adaptor 53BP1, which is an antagonist of homologous recombination (HR), in the context of proliferative retinopathy. In the model of retinopathy of prematurity (ROP), 53BP1-deficient mice displayed increased hypoxia-driven pathological neovascularization and tuft formation, accompanied by increased EC proliferation and reduced EC apoptosis, as compared with 53BP1-sufficient mice. In contrast, physiological retina angiogenesis was not affected by 53BP1 deficiency. Knockdown of 53BP1 in ECs in vitro also resulted in enhanced proliferation and reduced apoptosis of the cells under hypoxic conditions. Additionally, upon 53BP1 knockdown, ECs displayed increased HR rate in hypoxia. Consistently, treatment with an HR inhibitor reversed the hyper-proliferative angiogenic phenotype associated with 53BP1 deficiency in ROP. Thus, by unleashing HR, 53BP1 deletion increases pathological EC proliferation and neovascularization in the context of ROP. Our data shed light to a previously unknown interaction between the DNA repair response and pathological neovascularization in the retina.

Keywords

53BP1 - homologous recombination - angiogenesis - hypoxia - retinopathy - endothelium

Supplementary Material

 

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