Central role of RAGE-dependent neointimal expansion in arterial restenosis

J Clin Invest. 2003 Apr;111(7):959-72. doi: 10.1172/JCI17115.


Cellular proliferation, migration, and expression of extracellular matrix proteins and MMPs contribute to neointimal formation upon vascular injury. Wild-type mice undergoing arterial endothelial denudation displayed striking upregulation of receptor for advanced glycation end products (RAGE) in the injured vessel, particularly in activated smooth muscle cells of the expanding neointima. In parallel, two of RAGE's signal transducing ligands, advanced glycation end products (AGEs) and S100/calgranulins, demonstrated increased deposition/expression in the injured vessel wall. Blockade of RAGE, employing soluble truncated receptor or antibodies, or in homozygous RAGE null mice, resulted in significantly decreased neointimal expansion after arterial injury and decreased smooth muscle cell proliferation, migration, and expression of extracellular matrix proteins. A critical role for smooth muscle cell RAGE signaling was demonstrated in mice bearing a transgene encoding a RAGE cytosolic tail-deletion mutant, specifically in smooth muscle cells, driven by the SM22alpha promoter. Upon arterial injury, neointimal expansion was strikingly suppressed compared with that observed in wild-type littermates. Taken together, these data highlight key roles for RAGE in modulating smooth muscle cell properties after injury and suggest that RAGE is a logical target for suppression of untoward neointimal expansion consequent to arterial injury.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Arteriosclerosis
  • Cell Division
  • Cell Movement
  • Cells, Cultured
  • Coronary Restenosis
  • Dose-Response Relationship, Drug
  • Extracellular Matrix / metabolism
  • Heterozygote
  • Homozygote
  • Immunoblotting
  • Immunohistochemistry
  • In Situ Nick-End Labeling
  • Ligands
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Muscle, Smooth / cytology
  • Precipitin Tests
  • Promoter Regions, Genetic
  • RNA / metabolism
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic / metabolism*
  • Receptors, Immunologic / physiology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • S100 Proteins / metabolism
  • Signal Transduction
  • Time Factors
  • Tunica Intima / cytology*
  • Tunica Intima / pathology
  • Up-Regulation


  • Ligands
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic
  • S100 Proteins
  • RNA