MSC‐EVs Prevent Abdominal Aortic Aneurysm Formation by Inhibiting Perivascular Adipose Tissue‐Induced NET Release

Background: Perivascular adipose tissue (PVAT) envelops arteries and exerts paracrine effects, thereby modulating cardiovascular pathologies. Nevertheless, its precise role in abdominal aortic aneurysm (AAAs) pathogenesis remains elusive. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have been implicated in the regulation of neutrophil extracellular traps (NETs) formation. This investigation delineates PVAT's involvement in AAA, particularly in NETs regulation, and evaluates the modulatory impact of MSC-EVs on these processes. Methods: A comprehensive analysis of CT imaging and clinical datasets from AAA patients was undertaken. Subsequent RNA sequencing and transcriptomic profiling of PVAT from AAA animal models and controls were conducted. Both in vivo and in vitro assays were employed to determine whether PVAT-derived proteins influence NETs release within the abdominal aorta and contribute to AAA development. Additionally, MSC-EVs were administered via intravenous or intraperitoneal routes to assess their effects on PVAT accumulation and NETs formation. Results: A significant correlation was established between PVAT characteristics and clinical outcomes in AAA patients. Experimental findings reveal that PVAT-derived serum amyloid A (SAA) promotes PVAT accumulation and induces NETs release within the abdominal aorta during AAA formation. Intraperitoneal MSC-EVs administration mitigates AAA development by reducing PVAT accumulation, suppressing SAA expression in PVAT, and inhibiting NETs formation in the abdominal aorta. Conclusion: PVAT-derived SAA facilitates NETs formation during AAA pathogenesis. MSC-EVs, by targeting these mechanisms, offer a promising prophylactic strategy against AAA, opening new therapeutic avenues for future research.