Abstract 273: Shear Stress--Induced Atherosclerotic Plaque Regression Explained by Increased Macrophage Efferocytosis and Migration

Atherosclerotic plaques form in regions of low blood flow, whereas vessels exposed to high shear stress remain lesion-free. Using a model of arteriovenous fistula (AVF) in mice, we have previously shown that exposing established atherosclerotic plaques to elevated shear stress leads to lesion regression and increased matrix metalloproteinase (MMP) activity. MMP inhibition abolished shear stress-induced plaque regression and macrophage migration, suggesting that facilitating inflammatory cell movement within the plaque contributes to regression. We hypothesized that increased shear stress also leads to more efficient efferocytosis, another important hallmark of regression. LDLR-/- mice were placed on a high-fat diet. Sham and AVF surgery was performed at week 12 and mice were kept on a high-fat diet for a further 4 weeks (wk16). Control mice were sacrificed at wk12. The AVF procedure increases the shear stress in the brachiocephalic artery (BCA) but does not alter serum lipid levels. Using 3D echocardiography between wk12 and wk16, we observed that plaques progressed in the BCA of sham mice, whereas the AVF plaques regressed. Furthermore, the size of the necrotic core was significantly smaller in the AVF plaques than sham and control (P<0.05). This could be due to increased efferocytosis in the AVF, as verified using an in vitro model of the plaque environment. Endothelial cells (EC) were co-cultured with macrophages in a system wherein ECs are exposed to high or no shear stress and macrophages are exposed to the EC effluent. Uptake of apoptotic cells by macrophages was 50% higher in the high shear vs. static conditions (P<0.01). The MMP inhibitor, GM6001, had no effect on efferocytosis. However, a cytokine array on the co-culture effluent revealed interesting candidates. CCL3 and GMCSF, both of which have been associated with enhanced efferocytosis, were more highly expressed in high shear conditions vs. static. Our findings suggest that shear stress increases efferocytosis, leading to smaller necrotic cores through a mechanism that probably involves altered cytokine production. The combination of more efficient cell migration and efferocytosis in the presence of increased shear stress likely leads to plaque regression.