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 S.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 Aitken, David Robinson, Sanjay Patel, Mary M. Kavurma
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.