A disintegrin and metalloproteinase with thrombospondin motifs 4-targeted molecular magnetic resonance imaging for early detection of extracellular matrix remodeling in a porcine model of abdominal aortic aneurysm.

BACKGROUND: Abdominal aortic aneurysm (AAA) progression is driven by extracellular matrix (ECM) proteolysis and vascular smooth muscle cell loss, processes insufficiently captured by diameter-based surveillance. A disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4) is upregulated during early ECM remodeling, making it a compelling target for molecular imaging.

METHODS: Eighteen female German Landrace swine were enrolled. Eight animals underwent AAA induction and four served as controls; six animals were excluded due to procedural complications. Molecular 3 T MRI was performed at two and four weeks after induction following intravenous administration of an ADAMTS4-specific gadolinium probe (∼0.03 mmol/kg). Contrast-to-noise ratio (CNR) was calculated pre- and post-contrast. Aortic diameter was monitored by serial ultrasound. Ex vivo analysis included immunofluorescence, Western blotting, and laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS). Spearman correlation was used to evaluate relationships between MRI signal and molecular markers of ECM remodeling.

RESULTS: ΔCNR increased at two weeks (3.18 ± 0.56) and four weeks (4.35 ± 0.84) relative to controls (-0.14 ± 0.57; p = 0.017 and p = 0.046). ADAMTS4 immunofluorescence increased to 43.91 ± 9.48% at two weeks and 46.97 ± 4.50% at four weeks (control: 0.39 ± 0.03%). ΔCNR strongly correlated with ADAMTS4 (rs = 0.92, p < 0.001) and Galectin-3 (rs = 0.87, p < 0.001), and inversely with alpha-smooth muscle actin (rs = -0.90, p < 0.001), indicating that MRI signal reflects active proteolytic remodeling and smooth muscle cell depletion. LA-ICP-MS confirmed focal probe accumulation in regions of high ADAMTS4 expression.

CONCLUSION: ADAMTS4-targeted molecular MRI enables early, non-invasive detection of ongoing ECM remodeling in AAA and provides activity-based disease characterization beyond diameter-based assessment.