Susanne Feil1, Birgit Fehrenbacher1, Robert Lukowski1, Frank Essmann1, Klaus Schulze-Osthoff1, Martin Schaller1, Robert Feil2. 1. From the Interfakultäres Institut für Biochemie (S.F., F.E., K.S.-O., R.F.), Department of Dermatology (B.F., M.S.), and Pharmakologie, Toxikologie und Klinische Pharmazie (R.L.), University of Tübingen, Tübingen, Germany. 2. From the Interfakultäres Institut für Biochemie (S.F., F.E., K.S.-O., R.F.), Department of Dermatology (B.F., M.S.), and Pharmakologie, Toxikologie und Klinische Pharmazie (R.L.), University of Tübingen, Tübingen, Germany. robert.feil@uni-tuebingen.de.
Abstract
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, CreER(T2), 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 before the 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.
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, CreER(T2), 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 before the 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.