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Nat Commun. 2018 May 25;9(1):2073. doi: 10.1038/s41467-018-04447-7.

Integrin beta3 regulates clonality and fate of smooth muscle-derived atherosclerotic plaque cells.

Author information

1
Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, 06511, USA.
2
Department of Genetics, Yale University School of Medicine, New Haven, CT, 06511, USA.
3
Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, 06511, USA.
4
Pfizer, 610 Main Street, Cambridge, MA, 02139, USA.
5
Institute of Pharmacology and Toxicology, College of Pharmaceutical Science, Zhejiang University, Hangzhou, China.
6
Department of Surgery, Yale University School of Medicine, New Haven, CT, 06511, USA.
7
Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, 06511, USA. daniel.greif@yale.edu.
8
Department of Genetics, Yale University School of Medicine, New Haven, CT, 06511, USA. daniel.greif@yale.edu.

Abstract

Smooth muscle cells (SMCs) play a key role in atherogenesis. However, mechanisms regulating expansion and fate of pre-existing SMCs in atherosclerotic plaques remain poorly defined. Here we show that multiple SMC progenitors mix to form the aorta during development. In contrast, during atherogenesis, a single SMC gives rise to the smooth muscle-derived cells that initially coat the cap of atherosclerotic plaques. Subsequently, highly proliferative cap cells invade the plaque core, comprising the majority of plaque cells. Reduction of integrin β3 (Itgb3) levels in SMCs induces toll-like receptor 4 expression and thereby enhances Cd36 levels and cholesterol-induced transdifferentiation to a macrophage-like phenotype. Global Itgb3 deletion or transplantation of Itgb3(-/-) bone marrow results in recruitment of multiple pre-existing SMCs into plaques. Conditioned medium from Itgb3-silenced macrophages enhances SMC proliferation and migration. Together, our results suggest SMC contribution to atherogenesis is regulated by integrin β3-mediated pathways in both SMCs and bone marrow-derived cells.

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