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Deletion of NF-?B/RelA in Angiotensin II-Sensitive Mesenchymal Cells Blocks Aortic Vascular Inflammation and Abdominal Aortic Aneurysm Formation.


ABSTRACT: OBJECTIVE:Infusion of angiotensin II (Ang II) induces extracellular matrix remodeling and inflammation resulting in abdominal aortic aneurysms (AAAs) in normolipidemic mice. Although Ang II activates mesenchymal cells in the media and adventitia to become fibrogenic, the sentinel role of this mesenchymal population in modulating the inflammatory response and aneurysms is not known. We test the hypothesis that these fibrogenic mesenchymal cells play a critical role in Ang II-induced aortic wall vascular inflammation and AAA formation. APPROACH AND RESULTS:Ang II infusion increased phospho-Ser536-RelA and interleukin (IL)-6 immunostaining in the abdominal aorta. In addition, aortic mRNA transcripts of RelA-dependent cytokines IL-6 and IL-1? were significantly elevated suggesting that Ang II functionally activates RelA signaling. To test the role of mesenchymal RelA in AAA formation, we generated RelA-CKO mice by administering tamoxifen to double transgenic mice harboring RelA-flox alleles and tamoxifen-inducible Col1a2 promoter-driven Cre recombinase (Col1a2-CreERT). Tamoxifen administration to Col1a2-CreERT•mT/mG mice induced Cre expression and RelA depletion in aortic smooth muscle cells and fibroblasts but not in endothelial cells. Infusion of Ang II significantly increased abdominal aortic diameter and the incidence of AAA in RelA wild-type but not in RelA-CKO mice, independent of changes in systolic blood pressure. Furthermore, mesenchymal cell-specific RelA-CKO mice exhibited decreased expression of IL-6 and IL-1? cytokines and decreased recruitment of C68+ and F4/80lo•Ly6Chi monocytes during Ang II infusion. CONCLUSIONS:Fibrogenic mesenchymal RelA plays a causal role in Ang II-induced vascular inflammation and AAA in normolipidemic mice.

SUBMITTER: Ijaz T 

PROVIDER: S-EPMC5620126 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Deletion of NF-κB/RelA in Angiotensin II-Sensitive Mesenchymal Cells Blocks Aortic Vascular Inflammation and Abdominal Aortic Aneurysm Formation.

Ijaz Talha T   Sun Hong H   Pinchuk Irina V IV   Milewicz Dianna M DM   Tilton Ronald G RG   Brasier Allan R AR  

Arteriosclerosis, thrombosis, and vascular biology 20170817 10


<h4>Objective</h4>Infusion of angiotensin II (Ang II) induces extracellular matrix remodeling and inflammation resulting in abdominal aortic aneurysms (AAAs) in normolipidemic mice. Although Ang II activates mesenchymal cells in the media and adventitia to become fibrogenic, the sentinel role of this mesenchymal population in modulating the inflammatory response and aneurysms is not known. We test the hypothesis that these fibrogenic mesenchymal cells play a critical role in Ang II-induced aorti  ...[more]

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