We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Endothelial pannexin-1 channels modulate macrophage and smooth muscle cell activation in abdominal aortic aneurysm formation.
- Authors
Filiberto, Amanda C.; Spinosa, Michael D.; Elder, Craig T.; Su, Gang; Leroy, Victoria; Ladd, Zachary; Lu, Guanyi; Mehaffey, J. Hunter; Salmon, Morgan D.; Hawkins, Robert B.; Ravichandran, Kodi S.; Isakson, Brant E.; Upchurch Jr, Gilbert R.; Sharma, Ashish K.
- Abstract
Pannexin-1 (Panx1) channels have been shown to regulate leukocyte trafficking and tissue inflammation but the mechanism of Panx1 in chronic vascular diseases like abdominal aortic aneurysms (AAA) is unknown. Here we demonstrate that Panx1 on endothelial cells, but not smooth muscle cells, orchestrate a cascade of signaling events to mediate vascular inflammation and remodeling. Mechanistically, Panx1 on endothelial cells acts as a conduit for ATP release that stimulates macrophage activation via P2X7 receptors and mitochondrial DNA release to increase IL-1β and HMGB1 secretion. Secondly, Panx1 signaling regulates smooth muscle cell-dependent intracellular Ca2+ release and vascular remodeling via P2Y2 receptors. Panx1 blockade using probenecid markedly inhibits leukocyte transmigration, aortic inflammation and remodeling to mitigate AAA formation. Panx1 expression is upregulated in human AAAs and retrospective clinical data demonstrated reduced mortality in aortic aneurysm patients treated with Panx1 inhibitors. Collectively, these data identify Panx1 signaling as a contributory mechanism of AAA formation. Pannexin-1 ion channels on endothelial cells regulate vascular inflammation and remodeling to mediate aortic aneurysm formation. Pharmacological blockade of Pannexin-1 channels may offer translational therapeutic mitigation of aneurysmal pathology.
- Subjects
ABDOMINAL aortic aneurysms; MUSCLE cells; SMOOTH muscle; VASCULAR remodeling; VASCULAR endothelial cells; INTRACELLULAR calcium; ION channels
- Publication
Nature Communications, 2022, Vol 13, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-022-29233-4