Muscle-derived follistatin-like 1 functions to reduce neointimal formation after vascular injury

Cardiovasc Res. 2014 Jul 1;103(1):111-20. doi: 10.1093/cvr/cvu105. Epub 2014 Apr 17.


Aims: It is well-established that exercise diminishes cardiovascular risk, but whether humoral factors secreted by muscle confer these benefits has not been conclusively shown. We have shown that the secreted protein follistatin-like 1 (Fstl1) has beneficial actions on cardiac and endothelial function. However, the role of muscle-derived Fstl1 in proliferative vascular disease remains largely unknown. Here, we investigated whether muscle-derived Fstl1 modulates vascular remodelling in response to injury.

Methods and results: The targeted ablation of Fstl1 in muscle led to an increase in neointimal formation following wire-induced arterial injury compared with control mice. Conversely, muscle-specific Fstl1 transgenic (TG) mice displayed a decrease in the neointimal thickening following arterial injury. Muscle-specific Fstl1 ablation and overexpression increased and decreased, respectively, the frequency of BrdU-positive proliferating cells in injured vessels. In cultured human aortic smooth muscle cells (HASMCs), treatment with human FSTL1 protein decreased proliferation and migration induced by stimulation with PDGF-BB. Treatment with FSTL1 enhanced AMPK phosphorylation, and inhibition of AMPK abrogated the inhibitory actions of FSTL1 on HASMC responses to PDGF-BB. The injured arteries of Fstl1-TG mice exhibited an increase in AMPK phosphorylation, and administration of AMPK inhibitor reversed the anti-proliferative actions of Fstl1 on the vessel wall.

Conclusion: Our findings indicate that muscle-derived Fstl1 attenuates neointimal formation in response to arterial injury by suppressing SMC proliferation through an AMPK-dependent mechanism. Thus, the release of protein factors from muscle, such as Fstl1, may partly explain why the maintenance of muscle function can have a therapeutic effect on the cardiovascular system.

Keywords: AMPK; Fstl1; Myokine; Smooth muscle cell; Vascular remodelling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / antagonists & inhibitors
  • AMP-Activated Protein Kinases / metabolism
  • Animals
  • Becaplermin
  • Cell Movement
  • Cell Proliferation
  • Cells, Cultured
  • Disease Models, Animal
  • Femoral Artery / injuries*
  • Femoral Artery / pathology
  • Femoral Artery / physiopathology
  • Follistatin-Related Proteins / antagonists & inhibitors
  • Follistatin-Related Proteins / genetics
  • Follistatin-Related Proteins / physiology*
  • Gene Knockdown Techniques
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Muscle, Skeletal / physiology
  • Myocytes, Smooth Muscle / pathology
  • Myocytes, Smooth Muscle / physiology
  • Neointima / pathology*
  • Neointima / physiopathology*
  • Neointima / prevention & control
  • Proto-Oncogene Proteins c-sis / metabolism


  • Follistatin-Related Proteins
  • Fstl1 protein, mouse
  • Proto-Oncogene Proteins c-sis
  • FSTL1 protein, human
  • Becaplermin
  • AMP-Activated Protein Kinases