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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
› Institutsangaben Funding This work was supported by the Else-Kröner-Fresenius Stiftung.
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Publikationsverlauf

07. Juni 2018

19. November 2018

Publikationsdatum:
08. Januar 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

 

  • References

  • 1 Willis JR, Doan QV, Gleeson M. , et al. Vision-related functional burden of diabetic retinopathy across severity levels in the United States. JAMA Ophthalmol 2017; 135 (09) 926-932
    CrossrefPubMedGoogle Scholar
  • 2 Sapieha P, Joyal JS, Rivera JC. , et al. Retinopathy of prematurity: understanding ischemic retinal vasculopathies at an extreme of life. J Clin Invest 2010; 120 (09) 3022-3032
    CrossrefPubMedGoogle Scholar
  • 3 VanderVeen DK, Melia M, Yang MB, Hutchinson AK, Wilson LB, Lambert SR. Anti-vascular endothelial growth factor therapy for primary treatment of type 1 retinopathy of prematurity: a report by the American Academy of Ophthalmology. Ophthalmology 2017; 124 (05) 619-633
    CrossrefPubMedGoogle Scholar
  • 4 Das A, McGuire PG, Rangasamy S. Diabetic macular edema: pathophysiology and novel therapeutic targets. Ophthalmology 2015; 122 (07) 1375-1394
    CrossrefPubMedGoogle Scholar
  • 5 Osaadon P, Fagan XJ, Lifshitz T, Levy J. A review of anti-VEGF agents for proliferative diabetic retinopathy. Eye (Lond) 2014; 28 (05) 510-520
    CrossrefPubMedGoogle Scholar
  • 6 Manousaridis K, Talks J. Macular ischaemia: a contraindication for anti-VEGF treatment in retinal vascular disease?. Br J Ophthalmol 2012; 96 (02) 179-184
    CrossrefPubMedGoogle Scholar
  • 7 Siemerink MJ, Klaassen I, Van Noorden CJ, Schlingemann RO. Endothelial tip cells in ocular angiogenesis: potential target for anti-angiogenesis therapy. J Histochem Cytochem 2013; 61 (02) 101-115
    CrossrefPubMedGoogle Scholar
  • 8 Siemerink MJ, Augustin AJ, Schlingemann RO. Mechanisms of ocular angiogenesis and its molecular mediators. Dev Ophthalmol 2010; 46: 4-20
    PubMedGoogle Scholar
  • 9 Olcina M, Lecane PS, Hammond EM. Targeting hypoxic cells through the DNA damage response. Clin Cancer Res 2010; 16 (23) 5624-5629
    CrossrefPubMedGoogle Scholar
  • 10 Economopoulou M, Langer HF, Celeste A. , et al. Histone H2AX is integral to hypoxia-driven neovascularization. Nat Med 2009; 15 (05) 553-558
    CrossrefPubMedGoogle Scholar
  • 11 Okuno Y, Nakamura-Ishizu A, Otsu K, Suda T, Kubota Y. Pathological neoangiogenesis depends on oxidative stress regulation by ATM. Nat Med 2012; 18 (08) 1208-1216
    CrossrefPubMedGoogle Scholar
  • 12 Celeste A, Petersen S, Romanienko PJ. , et al. Genomic instability in mice lacking histone H2AX. Science 2002; 296 (5569): 922-927
    CrossrefPubMedGoogle Scholar
  • 13 Daley JM, Sung P. 53BP1, BRCA1, and the choice between recombination and end joining at DNA double-strand breaks. Mol Cell Biol 2014; 34 (08) 1380-1388
    CrossrefPubMedGoogle Scholar
  • 14 Bunting SF, Callén E, Wong N. , et al. 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks. Cell 2010; 141 (02) 243-254
    CrossrefPubMedGoogle Scholar
  • 15 Chapman JR, Taylor MR, Boulton SJ. Playing the end game: DNA double-strand break repair pathway choice. Mol Cell 2012; 47 (04) 497-510
    CrossrefPubMedGoogle Scholar
  • 16 Escribano-Díaz C, Orthwein A, Fradet-Turcotte A. , et al. A cell cycle-dependent regulatory circuit composed of 53BP1-RIF1 and BRCA1-CtIP controls DNA repair pathway choice. Mol Cell 2013; 49 (05) 872-883
    CrossrefPubMedGoogle Scholar
  • 17 Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nat Methods 2012; 9 (07) 671-675
    CrossrefPubMedGoogle Scholar
  • 18 Zong D, Callén E, Pegoraro G, Lukas C, Lukas J, Nussenzweig A. Ectopic expression of RNF168 and 53BP1 increases mutagenic but not physiological non-homologous end joining. Nucleic Acids Res 2015; 43 (10) 4950-4961
    CrossrefPubMedGoogle Scholar
  • 19 Ward IM, Minn K, van Deursen J, Chen J. p53 Binding protein 53BP1 is required for DNA damage responses and tumor suppression in mice. Mol Cell Biol 2003; 23 (07) 2556-2563
    CrossrefPubMedGoogle Scholar
  • 20 Economopoulou M, Bdeir K, Cines DB. , et al. Inhibition of pathologic retinal neovascularization by alpha-defensins. Blood 2005; 106 (12) 3831-3838
    CrossrefPubMedGoogle Scholar
  • 21 Economopoulou M, Avramovic N, Klotzsche-von Ameln A. , et al. Endothelial-specific deficiency of Junctional Adhesion Molecule-C promotes vessel normalisation in proliferative retinopathy. Thromb Haemost 2015; 114 (06) 1241-1249
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 22 Smith LE, Wesolowski E, McLellan A. , et al. Oxygen-induced retinopathy in the mouse. Invest Ophthalmol Vis Sci 1994; 35 (01) 101-111
    PubMedGoogle Scholar
  • 23 Klotzsche-von Ameln A, Cremer S, Hoffmann J. , et al. Endogenous developmental endothelial locus-1 limits ischaemia-related angiogenesis by blocking inflammation. Thromb Haemost 2017; 117 (06) 1150-1163
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 24 Budke B, Logan HL, Kalin JH. , et al. RI-1: a chemical inhibitor of RAD51 that disrupts homologous recombination in human cells. Nucleic Acids Res 2012; 40 (15) 7347-7357
    CrossrefPubMedGoogle Scholar
  • 25 Eberle D, Kurth T, Santos-Ferreira T, Wilson J, Corbeil D, Ader M. Outer segment formation of transplanted photoreceptor precursor cells. PLoS One 2012; 7 (09) e46305
    CrossrefPubMedGoogle Scholar
  • 26 Aiba Y, Kometani K, Hamadate M. , et al. Preferential localization of IgG memory B cells adjacent to contracted germinal centers. Proc Natl Acad Sci U S A 2010; 107 (27) 12192-12197
    CrossrefPubMedGoogle Scholar
  • 27 Sakaue-Sawano A, Kurokawa H, Morimura T. , et al. Visualizing spatiotemporal dynamics of multicellular cell-cycle progression. Cell 2008; 132 (03) 487-498
    CrossrefPubMedGoogle Scholar
  • 28 Gerhardt H, Golding M, Fruttiger M. , et al. VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J Cell Biol 2003; 161 (06) 1163-1177
    CrossrefPubMedGoogle Scholar
  • 29 Fernandez-Capetillo O, Celeste A, Nussenzweig A. Focusing on foci: H2AX and the recruitment of DNA-damage response factors. Cell Cycle 2003; 2 (05) 426-427
    PubMedGoogle Scholar
  • 30 Harding SM, Coackley C, Bristow RG. ATM-dependent phosphorylation of 53BP1 in response to genomic stress in oxic and hypoxic cells. Radiother Oncol 2011; 99 (03) 307-312
    CrossrefPubMedGoogle Scholar
  • 31 Ray Chaudhuri A, Nussenzweig A. The multifaceted roles of PARP1 in DNA repair and chromatin remodelling. Nat Rev Mol Cell Biol 2017; 18 (10) 610-621
    CrossrefPubMedGoogle Scholar
  • 32 Javle M, Curtin NJ. The role of PARP in DNA repair and its therapeutic exploitation. Br J Cancer 2011; 105 (08) 1114-1122
    CrossrefPubMedGoogle Scholar
  • 33 Ng N, Purshouse K, Foskolou IP, Olcina MM, Hammond EM. Challenges to DNA replication in hypoxic conditions. FEBS J 2018; 285 (09) 1563-1571
    CrossrefPubMedGoogle Scholar
  • 34 Aly A, Ganesan S. BRCA1, PARP, and 53BP1: conditional synthetic lethality and synthetic viability. J Mol Cell Biol 2011; 3 (01) 66-74
    CrossrefPubMedGoogle Scholar
  • 35 Ray Chaudhuri A, Callen E, Ding X. , et al. Replication fork stability confers chemoresistance in BRCA-deficient cells. Nature 2016; 535 (7612): 382-387
    PubMedGoogle Scholar