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R-Ras is a global regulator of vascular regeneration that suppresses intimal hyperplasia and tumor angiogenesis.

R-Ras is a small GTPase of the Ras family that regulates cell survival and integrin activity. Despite a number of in vitro studies, the in vivo function of R-Ras remains unclear. Here, we used R-Ras-null mice to explore the in vivo function of this small GTPase. Our results show a role for R-Ras as a regulator of vascular differentiation that primarily affects the remodeling of blood vessels. We show that R-Ras-null mice, although otherwise phenotypically normal, mount excessive vascular responses. We found that in vivo R-Ras expression is largely confined to fully differentiated smooth muscle cells, including those of blood vessels, and to endothelial cells. Challenging the R-Ras-null mice with arterial injury or tumor implantation showed exaggerated neointimal thickening in response to the injury and increased angiogenesis in the tumors. In wild-type mice, R-Ras expression was greatly reduced in hyperplastic neointimal smooth muscle cells and in angiogenic endothelial cells. Forced expression of activated R-Ras suppressed mitogenic and invasive activities of growth factor-stimulated vascular cells. These results establish an unexpected role for R-Ras in blood vessel homeostasis and suggest that R-Ras signaling may offer a target for therapeutic intervention in vascular diseases.

Pubmed ID: 16286923


  • Komatsu M
  • Ruoslahti E


Nature medicine

Publication Data

December 7, 2005

Associated Grants

  • Agency: NCI NIH HHS, Id: P01 CA82713
  • Agency: NCI NIH HHS, Id: P30 CA 30199
  • Agency: NCI NIH HHS, Id: R01 CA098162
  • Agency: NCI NIH HHS, Id: R01 CA79984
  • Agency: NCI NIH HHS, Id: T32 CA09579

Mesh Terms

  • Animals
  • DNA Primers
  • Endothelial Cells
  • Fluorescent Antibody Technique
  • GTP Phosphohydrolases
  • Gene Deletion
  • Genetic Vectors
  • Hyperplasia
  • Immunoblotting
  • Immunohistochemistry
  • Lentivirus
  • Mice
  • Myocytes, Smooth Muscle
  • Neoplasms
  • Neovascularization, Pathologic
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tunica Intima
  • ras Proteins