Endothelial pannexin-1 channels modulate macrophage and smooth muscle cell activation in abdominal aortic aneurysm formation

Amanda C. Filiberto, Michael D. Spinosa, Craig T. Elder, Gang Su, Victoria Leroy, Zachary Ladd, Guanyi Lu, J. Hunter Mehaffey, Morgan D. Salmon, Robert B. Hawkins, Kodi S. Ravichandran, Brant E. Isakson, Gilbert R. Upchurch and Ashish K. Sharma ()
Additional contact information
Amanda C. Filiberto: University of Florida
Michael D. Spinosa: University of Virginia
Craig T. Elder: University of Florida
Gang Su: University of Florida
Victoria Leroy: University of Florida
Zachary Ladd: University of Florida
Guanyi Lu: University of Florida
J. Hunter Mehaffey: University of Virginia
Morgan D. Salmon: University of Virginia
Robert B. Hawkins: University of Virginia
Kodi S. Ravichandran: University of Virginia
Brant E. Isakson: University of Virginia
Gilbert R. Upchurch: University of Florida
Ashish K. Sharma: University of Florida

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: 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.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29233-4

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DOI: 10.1038/s41467-022-29233-4

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