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2024

Sci Adv. 2024 Oct 4;10(40):eadn8760. doi: 10.1126/sciadv.adn8760. Epub 2024 Oct 4.

The generation of stable microvessels in ischemia is mediated by endothelial cell derived TRAIL

Siân P Cartland, Manisha S Patil, Elaina Kelland, Natalie Le, Lauren Boccanfuso, Christopher P Stanley, Pradeep Manuneedhi Cholan, Malathi I Dona, Ralph Patrick, Jordan McGrath, Qian Peter Su, Imala Alwis, Ruth Ganss, Joseph E Powell, Richard P Harvey, Alexander R Pinto, Thomas S Griffith, Jacky Loa, Sarah J Aitken, David A Robinson, Sanjay Patel, Mary M Kavurma

Heart Research Institute, The University of Sydney, Sydney, Australia. Centre for Peripheral Artery Disease, Heart Research Institute, Sydney, Australia. Baker Heart and Diabetes Institute, Melbourne, Australia. Victor Chang Cardiac Research Institute, Sydney, Australia. Royal Prince Alfred Hospital, Sydney, Australia. School of Biomedical Engineering, University of Technology, Sydney, Australia. Heart Research Institute, Sydney, Australia. Harry Perkins Institute of Medical Research, The University of Western Australia, Perth, Australia. Garvan-Weizmann Centre for Cellular Genomics, Sydney, Australia. UNSW Cellular Genomics Futures Institute, University of New South Wales, Sydney, Australia. School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, Australia. School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, Australia. University of Minnesota, Minneapolis, MN 55455, USA. Faculty of Medicine and Health, The University of Sydney, Sydney, Australia. Concord Institute of Academic Surgery, Concord Hospital, Sydney, Australia.

Service type: Knockout mice

Abstract

Reversal of ischemia is mediated by neo-angiogenesis requiring endothelial cell (EC) and pericyte interactions to form stable microvascular networks. We describe an unrecognized role for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in potentiating neo-angiogenesis and vessel stabilization. We show that the endothelium is a major source of TRAIL in the healthy circulation compromised in peripheral artery disease (PAD). EC deletion of TRAIL in vivo or in vitro inhibited neo-angiogenesis, pericyte recruitment, and vessel stabilization, resulting in reduced lower-limb blood perfusion with ischemia. Activation of the TRAIL receptor (TRAIL-R) restored blood perfusion and stable blood vessel networks in mice. Proof-of-concept studies showed that Conatumumab, an agonistic TRAIL-R2 antibody, promoted vascular sprouts from explanted patient arteries. Single-cell RNA sequencing revealed heparin-binding EGF-like growth factor in mediating EC-pericyte communications dependent on TRAIL. These studies highlight unique TRAIL-dependent mechanisms mediating neo-angiogenesis and vessel stabilization and the potential of repurposing TRAIL-R2 agonists to stimulate stable and functional microvessel networks to treat ischemia in PAD.

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