Bone Marrow–Derived Smooth Muscle–Like Cells Are Infrequent in Advanced Primary Atherosclerotic Plaques but Promote Atherosclerosis

Objective—Although vascular smooth muscle cells (VSMCs) provide the major structural integrity of atherosclerotic plaques, their origin has been questioned. In particular, although some studies identified plaque VSMCs originating from bone marrow or peripheral blood, their frequency is controversial and their function unknown. We used genetic tracking of cell fate through smooth muscle cell (SMC)–specific LacZ reporter activity and VSMC-selective apoptosis to investigate the frequency, distribution, and role of marrow-derived VSMCs in atherogenesis. Methods and Results—Cultured mouse bone marrow–derived smooth muscle–like cells expressed SMC markers and functional SMC promoter-driven transgenes over time. Transplantation of apolipoprotein E (ApoE)/ mice with smooth muscle myosin heavy chain–Cre/ROSA26R/ApoE/ marrow showed that 0.70.14 % cells expressed LacZ in atherosclerotic plaques, located superficially in early plaques, and in necrotic cores but not fibrous caps of advanced lesions. Cells expressing both progenitor and SMC markers showed a similar distribution and frequency. Apoptosis of marrow-derived SMC-like cells transplanted from SM22–human diphtheria toxin receptor/ApoE/ mice retarded atherogenesis, with reduced plaque macrophage content. Cultured marrow-derived SMC-like cells secreted proinflam-matory cytokines and promoted macrophage migration, VSMC proliferation, and collagen synthesis. Conclusion—Bone marrow – derived SMC-like cells are infrequent in advanced primary atherosclerotic plaques and absent in fibrous caps. However, these cells secrete proinflammatory cytokines and mitogens and promot