Journal article

Blocking endothelial apoptosis revascularizes the retina in a model of ischemic retinopathy

Zoe L Grant, Lachlan Whitehead, Vickie HY Wong, Zheng He, Richard Y Yan, Abigail R Miles, Andrew Benest, David O Bates, Claudia Prahst, Katie Bentley, Bang Bui, Robert CA Symons, Leigh Coultas

Journal of Clinical Investigation | AMER SOC CLINICAL INVESTIGATION INC | Published : 2020

Abstract

Aberrant, neovascular retinal blood vessel growth is a vision-threatening complication in ischemic retinal diseases. It is driven by retinal hypoxia frequently caused by capillary nonperfusion and endothelial cell (EC) loss. We investigated the role of EC apoptosis in this process using a mouse model of ischemic retinopathy, in which vessel closure and EC apoptosis cause capillary regression and retinal ischemia followed by neovascularization. Protecting ECs from apoptosis in this model did not prevent capillary closure or retinal ischemia. Nonetheless, it prevented the clearance of ECs from closed capillaries, delaying vessel regression and allowing ECs to persist in clusters throughout the..

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Grants

Awarded by British Heart Foundation


Awarded by Royal Society


Awarded by NHMRC, Australia


Awarded by Australian Research Council


Awarded by Medical Research Council


Awarded by NIH National Eye Institute


Funding Acknowledgements

The authors thank Genentech Inc. for provision of the B204.1.1 antibody; Gou Young Koh (KAIST, Daejeon) for provision of the anti-ANG2 antibodies ABA and 4H10; Steven A. Stacker (Peter MacCallum Cancer Centre, Melbourne) for provision of the palivizumab antibody; Douglas Green (St Jude Children's Research Hospital, Memphis) for Bax conditional allele mice; Masashi Yanagisawa (UT Southwestern) for Tie2-Cre mice; Razqallah Hakem (University of Toronto) for caspase-8<SUP>-/-</SUP> mice; Warren Alexander (Walter and Eliza Hall Institute) for Mlkl-/and double-knockout caspase-8<SUP>-/-</SUP> Mlkl<SUP>-/-</SUP> mice; Ralf H. Adams (Max Planck Institute, Munster) for Cdh5(PAC)-CreERT2 mice; Glenna-Faye Dabrowski, Melissa Pritchard, Jaclyn Gilbert, and Dannielle Cooper for expert animal care; and Steven Stacker (Peter MacCallum Cancer Centre), Andreas Strasser (Walter and Eliza Hall Institute), Anne K. Voss (Walter and Eliza Hall Institute), and members of the Development and Cancer Division (Walter and Eliza Hall Institute) for informative discussion. This work was made possible through Victorian State Government Operational Infrastructure Support and the Australian Government National Health and Medical Research Council (NHMRC) Independent Research Institute Neuroscience Foundation. AVB and DOB were supported by the British Heart Foundation (grant PG/18/31/33759 to DOB) and the Royal Society (grant RGS\R1\191221).Infrastructure Support Scheme. This work was supported by the NHMRC, Australia (Project Grant 1125536 to LC); the Australian Research Council (Future Fellowships 110100891 to LC); an Australian Government Research Training Program Scholarship (to ZLG); the L.E.W. Carty Charitable Fund (to LC); the Medical Research Council (MR/K013157/1 to DOB); NIH National Eye Institute 1 R21 EY027067-01 (to KB and CP); the Kjell and Marta Beijers Foundation (to KB); and the Royal Melbourne Hospital