M1 Macrophage-Derived Exosomal miR-155-5p Exacerbates Aortic Dissection Progression via SMAD5-Mediated Regulation of Vascular Smooth Muscle Cell Phenotype

Background Aortic dissection (AD) constitutes a critical and potentially lethal cardiovascular emergency, yet its underlying pathogenesis remains largely obscure. The present research aimed to elucidate the contribution of exosomes derived from M1 macrophages—particularly those carrying a high load of miR-155-5p—to the exacerbation of AD. Methods Macrophage infiltration and exosome distribution were evaluated in human and mouse AD tissues. Exosomes were isolated from M1-polarized RAW264.7 macrophages and characterized. Primary mouse VSMCs were treated in vitro, while a β-aminopropionitrile (BAPN)--established murine AD model was used for in vivo studies. Interventions included GW4869 and engineered exosomes loaded with Antago-miR-155-5p. Techniques included qRT-PCR, Western blotting, luciferase assays, RNA-FISH, and histological analyses. Results M1 macrophages and their exosomes were markedly enriched in AD tissues and colocalized with macrophage markers. M1-derived exosomes were internalized by VSMCs, significantly downregulated contractile indicators (CNN, α-SMA, MYOCD, SM22α), and induced synthetic phenotypic switching via exosomal miR-155-5p targeting SMAD5 (luciferase assay). In BAPN-induced mice, inhibition of exosome secretion (GW4869) or treatment with Antago-miR-155-5p-loaded exosomes significantly reduced AD incidence (from 86.7% to 46.7%), mortality, aortic dilation, elastic fiber fragmentation, and restored contractile marker and SMAD5 expression. Conclusions Exosomal miR-155-5p originating from M1 macrophages facilitates AD development through targeting SMAD5 and driving VSMC phenotypic switching. Engineered Antago-miR-155-5p exosomes represent a novel, effective therapeutic strategy for mitigating AD, providing a foundation for exosome-based RNA interference in vascular diseases.