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

Nature medicine | Dec 7, 2005

http://www.ncbi.nlm.nih.gov/pubmed/16286923

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 RIS Download

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

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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

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