Transdifferentiation of Vascular Smooth Muscle Cells to Macrophage-Like Cells During Atherogenesis
Rationale: Atherosclerosis is a widespread and devastating disease, but the origins of cells within atherosclerotic plaques are not well defined.
Objective: To investigate the specific contribution of vascular smooth muscle cells (SMCs) to atherosclerotic plaque formation by genetic inducible fate mapping in mice.
Methods and Results: Vascular SMCs were genetically pulse-labeled using the tamoxifen-dependent Cre recombinase, CreERT2, expressed from the endogenous SM22α locus combined with Cre-activatable reporter genes that were integrated into the ROSA26 locus. Mature SMCs in the arterial media were labeled by tamoxifen treatment of young apolipoprotein E-deficient mice prior to development of atherosclerosis and then their fate was monitored in older atherosclerotic animals. We found that medial SMCs can undergo clonal expansion and convert to macrophage-like cells that have lost classic SMC marker expression and make up a major component of advanced atherosclerotic lesions.
Conclusions: This study provides strong in vivo evidence for smooth muscle-to-macrophage transdifferentiation and supports an important role of SMC plasticity in atherogenesis. Targeting this type of SMC phenotypic conversion might be a novel strategy for the treatment of atherosclerosis as well as other diseases with a smooth muscle component.
- Cre/lox system
- lineage tracing
- vascular smooth muscle
- genetics, transgenic models
- Received June 18, 2014.
- Revision received July 19, 2014.
- Accepted July 25, 2014.