Extensive Proliferation of a Subset of Differentiated, yet Plastic, Medial Vascular Smooth Muscle Cells Contributes to Neointimal Formation in Mouse Injury and Atherosclerosis Models.
BACKGROUND
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 whether 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.


RESULTS
Using multicolor 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 contributes to both alpha smooth muscle actin (aSma)-positive fibrous cap and Mac3-expressing macrophage-like plaque core cells. Costaining 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 the expression of VSMC markers and the 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 results in the observed VSMC accumulation after injury and in atherosclerotic plaques. Therapeutic targeting of these hyperproliferating VSMCs might effectively reduce vascular disease without affecting vascular integrity.
From the Cardiovascular Medicine Division, Department of Medicine (J.C., J.L.H., H.Y., K.F., M.R.B., H.F.J.), Cavendish Laboratory, Department of Physics (B.D.S.), The Wellcome Trust/Cancer Research UK Gurdon Institute (B.D.S.), and Wellcome Trust-Medical Research Council Stem Cell Institute (B.D.S.), University of Cambridge, United Kingdom; and The Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom (V.M.N.).
Joel
J
Chappell
From the Cardiovascular Medicine Division, Department of Medicine (J.C., J.L.H., H.Y., K.F., M.R.B., H.F.J.), Cavendish Laboratory, Department of Physics (B.D.S.), The Wellcome Trust/Cancer Research UK Gurdon Institute (B.D.S.), and Wellcome Trust-Medical Research Council Stem Cell Institute (B.D.S.), University of Cambridge, United Kingdom; and The Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom (V.M.N.).
Jennifer L
JL
Harman
From the Cardiovascular Medicine Division, Department of Medicine (J.C., J.L.H., H.Y., K.F., M.R.B., H.F.J.), Cavendish Laboratory, Department of Physics (B.D.S.), The Wellcome Trust/Cancer Research UK Gurdon Institute (B.D.S.), and Wellcome Trust-Medical Research Council Stem Cell Institute (B.D.S.), University of Cambridge, United Kingdom; and The Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom (V.M.N.).
Vagheesh M
VM
Narasimhan
From the Cardiovascular Medicine Division, Department of Medicine (J.C., J.L.H., H.Y., K.F., M.R.B., H.F.J.), Cavendish Laboratory, Department of Physics (B.D.S.), The Wellcome Trust/Cancer Research UK Gurdon Institute (B.D.S.), and Wellcome Trust-Medical Research Council Stem Cell Institute (B.D.S.), University of Cambridge, United Kingdom; and The Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom (V.M.N.).
Haixiang
H
Yu
From the Cardiovascular Medicine Division, Department of Medicine (J.C., J.L.H., H.Y., K.F., M.R.B., H.F.J.), Cavendish Laboratory, Department of Physics (B.D.S.), The Wellcome Trust/Cancer Research UK Gurdon Institute (B.D.S.), and Wellcome Trust-Medical Research Council Stem Cell Institute (B.D.S.), University of Cambridge, United Kingdom; and The Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom (V.M.N.).
Kirsty
K
Foote
From the Cardiovascular Medicine Division, Department of Medicine (J.C., J.L.H., H.Y., K.F., M.R.B., H.F.J.), Cavendish Laboratory, Department of Physics (B.D.S.), The Wellcome Trust/Cancer Research UK Gurdon Institute (B.D.S.), and Wellcome Trust-Medical Research Council Stem Cell Institute (B.D.S.), University of Cambridge, United Kingdom; and The Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom (V.M.N.).
Benjamin D
BD
Simons
From the Cardiovascular Medicine Division, Department of Medicine (J.C., J.L.H., H.Y., K.F., M.R.B., H.F.J.), Cavendish Laboratory, Department of Physics (B.D.S.), The Wellcome Trust/Cancer Research UK Gurdon Institute (B.D.S.), and Wellcome Trust-Medical Research Council Stem Cell Institute (B.D.S.), University of Cambridge, United Kingdom; and The Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom (V.M.N.).
Martin R
MR
Bennett
From the Cardiovascular Medicine Division, Department of Medicine (J.C., J.L.H., H.Y., K.F., M.R.B., H.F.J.), Cavendish Laboratory, Department of Physics (B.D.S.), The Wellcome Trust/Cancer Research UK Gurdon Institute (B.D.S.), and Wellcome Trust-Medical Research Council Stem Cell Institute (B.D.S.), University of Cambridge, United Kingdom; and The Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom (V.M.N.). hfj22@cam.ac.uk.
Helle F
HF
Jørgensen
D000818:Animals; D050197:Atherosclerosis / Q000473:pathology / Q000503:physiopathology*; D049109:Cell Proliferation / Q000502:physiology*; D004195:Disease Models, Animal; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000502:physiology*; D032389:Myocytes, Smooth Muscle / Q000502:physiology*; D058426:Neointima / Q000473:pathology / Q000503:physiopathology*; D057772:Vascular System Injuries / Q000473:pathology / Q000503:physiopathology*
atherosclerosis; lineage-tracing; macrophages; neointima; phenotype; vascular diseases vascular smooth muscle
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