Search

Abdominal aortic aneurysm (AAA) formation is characterized by inflammation, leukocyte infiltration, and vascular remodeling. Resolvin D1 (RvD1) is derived from ω‐3 polyunsaturated fatty acids and is involved in the resolution phase of chronic inflammatory diseases. The aim of this study was to decipher the protective role of RvD1 via formyl peptide receptor 2 (FPR2) receptor signaling in attenuating abdominal aortic aneurysms (AAA). The elastase‐treatment model of AAA in C57BL/6 (WT) mice and human AAA tissue was used to confirm our hypotheses. Elastase‐treated FPR2−/− mice had a significant increase in aortic diameter, proinflammatory cytokine production, immune cell infiltration (macrophages and neutrophils), elastic fiber disruption, and decrease in smooth muscle cell α‐actin expression compared to elastase‐treated WT mice. RvD1 treatment attenuated AAA formation, aortic inflammation, and vascular remodeling in WT mice, but not in FPR2−/− mice. Importantly, human AAA tissue demonstrated significantly decreased FPR2 mRNA expression compared to non‐aneurysm human aortas. Mechanistically, RvD1/FPR2 signaling mitigated p47phox phosphorylation and prevented hallmarks of ferroptosis, such as lipid peroxidation and Nrf2 translocation, thereby attenuating HMGB1 secretion. Collectively, this study demonstrates RvD1‐mediated immunomodulation of FPR2 signaling on macrophages to mitigate ferroptosis and HMGB1 release, leading to resolution of aortic inflammation and remodeling during AAA pathogenesis. [ABSTRACT FROM AUTHOR]

Abdominal aortic aneurysm (AAA) formation is characterized by inflammation, leukocyte infiltration, and vascular remodeling. This study investigates the role of TRPV4 channels, which are transmembrane calcium channels that can regulate vascular tone, in modulating AAA formation. The elastase‐treatment model of AAA in C57BL6 (WT) mice and Angiotensin II treatment model in ApoE−/− mice were used to confirm our hypotheses. The administration of a specific TRPV4 antagonist, GSK2193874, in elastase‐treated WT mice and in AngII‐treated ApoE−/− mice caused a significant attenuation of aortic diameter, decrease in pro‐inflammatory cytokines (IL‐1β, IL‐6, IL‐17, MCP‐1, MIP‐1α, MIP‐2, RANTES, and TNF‐α), inflammatory cell infiltration (CD3 + T cells, macrophages, and neutrophils), elastic fiber disruption, and an increase in smooth muscle cell α‐actin expression compared to untreated mice. Similarly, elastase‐treated TRPV4−/− mice had a significant decrease in AAA formation, aortic inflammation, and vascular remodeling compared to elastase‐treated WT mice on Day 14. In vitro studies demonstrated that the inhibition of TRPV4 channels mitigates aortic smooth muscle cell‐dependent inflammatory cytokine production as well as decreases neutrophil transmigration through aortic endothelial cells. Therefore, our results suggest that TRPV4 antagonism can attenuate aortic inflammation and remodeling via decreased smooth muscle cell activation and neutrophil transendothelial migration during AAA formation. [ABSTRACT FROM AUTHOR]