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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / cytology
  • Aorta / pathology
  • Atherosclerosis / pathology*
  • Atherosclerosis / surgery
  • Bone Marrow Transplantation
  • Cell Movement
  • Cell Proliferation*
  • Cell Transdifferentiation
  • Cells, Cultured
  • Cholesterol / metabolism
  • Disease Models, Animal
  • Female
  • Humans
  • Integrin beta3 / physiology*
  • Macrophages / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout, ApoE
  • Muscle, Smooth, Vascular / cytology
  • Myocytes, Smooth Muscle / metabolism*
  • Myocytes, Smooth Muscle / pathology
  • Plaque, Atherosclerotic / pathology*
  • Plaque, Atherosclerotic / surgery

Substances

  • Integrin beta3
  • Cholesterol