Extensive Proliferation of a Subset of Differentiated, Yet Plastic, Medial Vascular Smooth Muscle Cells Contribute to Neointimal Formation in Mouse Injury and Atherosclerosis Models
Rationale: Vascular smooth muscle cell (VSMC) accumulation is a hallmark of atherosclerosis and vascular injury. However, fundamental aspects of proliferation and the phenotypic changes within individual VSMCs, which underlie vascular disease remain unresolved. In particular, it is not known if all VSMCs proliferate and display plasticity, or whether individual cells can switch to multiple phenotypes.
Objective: To assess whether proliferation and plasticity in disease is a general characteristic of VSMCs or a feature of a subset of cells.
Methods and Results: Using multi-color lineage labeling, we demonstrate that VSMCs in injury-induced neointimal lesions and in atherosclerotic plaques are oligoclonal, derived from few expanding cells. Lineage tracing also revealed that the progeny of individual VSMCs contribute to both alpha smooth muscle actin (aSma)-positive fibrous cap and Mac-3-expressing macrophage-like plaque core cells. Co-staining for phenotypic markers further identified a double-positive aSma+ Mac3+ cell population, which is specific to VSMC-derived plaque cells. In contrast, VSMC-derived cells generating the neointima after vascular injury generally retained expression of VSMC markers and upregulation of Mac3 was less pronounced. Monochromatic regions in atherosclerotic plaques and injury-induced neointima did not contain VSMC-derived cells expressing a different fluorescent reporter protein, suggesting that proliferation-independent VSMC migration does not make a major contribution to VSMC accumulation in vascular disease.
Conclusions:We demonstrate that extensive proliferation of a low proportion of highly plastic VSMCs result in the observed VSMC accumulation after injury and in atherosclerotic plaques. Therapeutic targeting of these hyper-proliferating VSMCs might effectively reduce vascular disease without affecting vascular integrity.
- multi-color lineage tracing
- carotid ligation
- vascular smooth muscle
- vascular surgery
- carotid occlusive disease
- vascular disease
- Received August 23, 2016.
- Revision received September 13, 2016.
- Accepted September 27, 2016.
Circulation Research is published on behalf of the American Heart Association, Inc., by Wolters Kluwer. This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.