Abstract 13097: Calcified Vascular Smooth Muscle Cells Promote Macrophage Infiltration In Atherosclerosis
Intimal macrophage infiltration and vascular smooth muscle cell (VSMC) calcification contribute significantly to the pathogenesis of atherosclerosis. However, little is known of the crosstalk between these two major vascular cell-types in atherosclerosis. We have reported an essential role of the osteogenic transcription factor Runx2 in VSMC calcification. In addition, Runx2 bound to the promoter and induced the expression of RANKL, the key regulator for osteoclast, a cell type also found in the vicinity of bone-like structures in atherosclerosis. VSMC-expressed RANKL induced migration and osteoclastic differentiation of macrophages in a co-culture system. The present studies investigated the interaction between calcified VSMC and macrophages in vivo. High-fat diet induced atherosclerosis and vascular calcification in apoE−/− mice. Increased Runx2 and RANKL were detected in the calcified arteries closely associated with CD68+-macrophages and multinucleated cells with TRAP+, an osteoclast marker. To further evaluate the interaction of calcified VSMC and macrophages, apoE−/− (Ly5.2) mice that had been fed chow or high-fat diets for 8 weeks were lethally irradiated (950 RADS), transplanted with bone marrow from gender-matched apoE−/− (Ly5.1) mice, and subsequently maintained on chow or high-fat diets for 12 weeks. Increased atherosclerosis and vascular calcification were confirmed by en face staining with Sudan Red and aortic staining with Alizarin Red. Importantly, increased donor-derived (Ly5.1+) CD68+ macrophages were identified in the calcified areas with enhanced expression of Runx2/RANKL, indicating macrophage infiltration into the vicinity of calcified VSMC. Furthermore, TRAP+ osteoclastic cells were identified within the CD68+ macrophage areas associated with calcification. Our studies demonstrated that upregulation of Runx2/RANKL was associated with vascular calcification in vivo. Increased macrophage infiltration and the presence of TRAP+ osteoclast-like cells were identified in the vicinity of Runx2/RANKL+ calcified areas in the atherosclerotic lesions. Our studies thus provide novel molecular insights into the functional interactive roles of VSMC and macrophages in the pathogenesis of atherosclerosis.
- © 2010 by American Heart Association, Inc.