Tumor necrosis factor-like weak inducer of apoptosis or Fn14 deficiency reduce elastase perfusion-induced aortic abdominal aneurysm in mice

Background-abdominal aortic aneurysm (aaa) involves leukocyte recruitment,inflammatory cytokine production,vascular cell apoptosis,neovascularization,and vascular remodeling,all of which contribute to aortic dilatation. tumor necrosis factor-like weak inducer of apoptosis (tweak) is a cytokine implicated in proinflammatory responses,angiogenesis,and matrix degradation but its role in aaa formation is currently unknown. methods and results-experimental aaa with aortic elastase perfusion in mice was induced in wild-type (wt),tweak deficient (tweak ko),or fn14-deficient (fn14 ko) mice. tweak or fn14 ko deficiency reduced aortic expansion,lesion macrophages,cd3+ t cells,neutrophils,cd31+ microvessels,ccl2 and ccl5 chemokines expression,and mmp activity after 14 days postperfusion. tweak and fn14 ko mice also showed a reduced loss of medial vascular smooth muscle cells (vsmc) that was related to a reduced number of apoptotic cells in these animals compared with wt mice. aortas from wt animals present a higher disruption of the elastic layer and mmp activity than those from tweak or fn14 ko mice,indicating a diminished vascular remodeling in ko animals. in vitro experiments unveiled that tweak induces ccl5 secretion and mmp-9 activation in both vsmc and bone marrow-derived macrophages,and decrease vsmc viability,effects dependent on fn14. conclusions-tweak/fn14 axis participates in aaa formation by promoting lesion inflammatory cell accumulation,angiogenesis,matrix-degrading protease expression,and vascular remodeling. blocking tweak/fn14 interaction could be a new target for the treatment of aaa. © 2014 the authors.