Axl modulates immune activation of smooth muscle cells in vein graft remodeling

Am J Physiol Heart Circ Physiol. 2015 Sep 15;309(6):H1048-58. doi: 10.1152/ajpheart.00495.2015. Epub 2015 Aug 14.

Abstract

The pathophysiological mechanisms of the immune activation of smooth muscle cells are not well understood. Increased expression of Axl, a receptor tyrosine kinase, was recently found in arteries from patients after coronary bypass grafts. In the present study, we hypothesized that Axl-dependent immune activation of smooth muscle cells regulates vein graft remodeling. We observed a twofold decrease in intimal thickening after vascular and systemic depletion of Axl in vein grafts. Local depletion of Axl had the greatest effect on immune activation, whereas systemic deletion of Axl reduced intima due to an increase in apoptosis in vein grafts. Primary smooth muscle cells isolated from Axl knockout mice had reduced proinflammatory responses by prevention of the STAT1 pathway. The absence of Axl increased suppressor of cytokine signaling (SOCS)1 expression in smooth muscle cells, a major inhibitory protein for STAT1. Ultrasound imaging suggested that vascular depletion of Axl reduced vein graft stiffness. Axl expression determined the STAT1-SOCS1 balance in vein graft intima and progression of the remodeling. The results of this investigation demonstrate that Axl promotes STAT1 signaling via inhibition of SOCS1 in activated smooth muscle cells in vein graft remodeling.

Keywords: Axl; inflammation; smooth muscle cell; vascular remodeling.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Aorta / cytology
  • Apoptosis
  • Axl Receptor Tyrosine Kinase
  • Carotid Arteries / immunology
  • Carotid Arteries / metabolism
  • Carotid Arteries / surgery
  • Mice
  • Mice, Knockout
  • Muscle, Smooth, Vascular / immunology*
  • Muscle, Smooth, Vascular / metabolism
  • Myocytes, Smooth Muscle / immunology*
  • Myocytes, Smooth Muscle / metabolism
  • Proto-Oncogene Proteins / genetics*
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Reverse Transcriptase Polymerase Chain Reaction
  • STAT1 Transcription Factor / immunology*
  • STAT1 Transcription Factor / metabolism
  • Signal Transduction
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling Proteins / immunology*
  • Suppressor of Cytokine Signaling Proteins / metabolism
  • Transcriptome
  • Tunica Intima / immunology
  • Tunica Intima / metabolism
  • Vascular Remodeling / immunology*
  • Vascular Stiffness / immunology*
  • Vena Cava, Inferior / immunology
  • Vena Cava, Inferior / metabolism
  • Vena Cava, Inferior / transplantation

Substances

  • Proto-Oncogene Proteins
  • STAT1 Transcription Factor
  • Socs1 protein, mouse
  • Stat1 protein, mouse
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Receptor Protein-Tyrosine Kinases
  • Axl Receptor Tyrosine Kinase
  • AXL receptor tyrosine kinase, mouse