**Background:** Blood flow is a key regulator of atherosclerosis. Disturbed blood flow promotes plaque development, while normal (unidirectional) flow is atheroprotective. However, whether restoring normal blood flow in already-diseased arteries could be therapeutic had not been directly tested. The authors hypothesized that restoration of normal blood flow within atherosclerotic arteries promotes plaque stabilization.
**Methods:** Female ApoE⁻/⁻ mice (n=75) were placed on an atherogenic diet and instrumented with a blood flow-modifying cuff around the left common carotid artery to induce plaque development. After 5 weeks (intermediate plaque stage), mice were randomized into five groups: (1) 5U – sacrificed at week 5; (2) 9U – untreated, cuff maintained until week 9; (3) 9A – atorvastatin daily (0.22 mg, ~10 mg/kg) from week 5 to 9 with cuff maintained; (4) 9D – decuffed at week 5, no cuff for 4 additional weeks; (5) 9AD – combination of atorvastatin and decuffing. Serial MRI (9.4T) and Doppler ultrasound were performed at weeks −1, 1, 4, 7, and 9 to assess lumen area and blood velocity. CFD modeling was used to compute wall shear stress at peak systole (pWSS) and oscillatory shear index (OSI). Histology assessed plaque burden (oil red O), lipids (oil red O), macrophages (CD68 immunofluorescence), and collagen (picrosirius red).
**Key Results:** In the unstable (upstream) plaque region, decuffed mice (9D) showed significantly lower lipid content (4.8 ± 4.5%) versus 5U (8.9 ± 2.3%, p=0.04) and 9U (17.2 ± 9.4%, p=0.005); lower macrophage content (9.3 ± 6.9%) versus 5U (25.9 ± 8.5%, p=0.0002) and 9U (33.8 ± 15.5%, p=0.001); and higher collagen content (9.3 ± 3.1%) versus 5U (3.8 ± 2.1%, p=0.004) and 9U (4.9 ± 2.0%, p=0.005). The 9A group showed similar improvements, with no significant differences between 9A and 9D. The combination group (9AD) had the highest collagen content (15.7 ± 4.2%), significantly higher than 9A (8.2 ± 5.4%, p=0.01) and 9D (9.3 ± 3.1%, p=0.008). In the stable (downstream) region, 9AD had the highest collagen (24.5 ± 6.2%), significantly higher than 5U (9.3 ± 4.3%, p<0.0001), 9U (9.6 ± 5.4%, p<0.0001), and 9D (17.1 ± 5.0%, p=0.03). Plaque burden was significantly reduced only in the 9AD group versus 9U in both unstable (22.7 ± 18.0% vs 43.5 ± 12.8%, p=0.02) and stable (28.9 ± 10.7% vs 47.2 ± 13.6%, p=0.007) regions. MRI showed that lumen area at maximum stenosis in 9D mice recovered from 13.7 ± 5.2% of baseline at week 1 to 84.3 ± 18.1% at week 9 (vs 97.3 ± 14.6% in control, p=0.07). Blood velocity recovered from 55.9 ± 8.8% of baseline at week 1 to 82.6 ± 20.2% at week 9 (vs 93.9 ± 17.7% in control, p=0.31). CFD showed that pWSS in the upstream region was restored from 7.8 ± 2.3 Pa (cuffed) to 12.8 ± 2.3 Pa (decuffed), not significantly different from baseline (14.4 ± 3.3 Pa, p=0.37). OSI in the downstream region was 0.18 ± 0.08 at week 1 versus 0.00 ± 0.00 at both baseline and week 9 (p=0.003 for both).
**Clinical Implications:** This study provides the first direct causal evidence that restoring normal blood flow promotes plaque stabilization, with effects comparable to atorvastatin. The additive benefit of combining flow restoration with statin therapy suggests they act through different signaling pathways. These findings motivate development of biomechanical or pharmacologic approaches that leverage mechanosensitive pathways in atherosclerosis. Limitations include use of only female mice, assessment at intermediate plaque stage, a 4-week therapeutic window, and lack of direct shear-to-histology correlation.