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.
Komatsu
Masanobu
M
Burnham Institute for Medical Research, Cancer Research Center, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.
Ruoslahti
Erkki
E
D000818:Animals; D017931:DNA Primers; D042783:Endothelial Cells / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D005822:Genetic Vectors; D006965:Hyperplasia / Q000378:metabolism / Q000473:pathology; D015151:Immunoblotting; D007150:Immunohistochemistry; D016086:Lentivirus; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D009369:Neoplasms / Q000098:blood supply*; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
D017931:DNA Primers; D020558:GTP Phosphohydrolases; C513254:Rras protein, mouse; D018631:ras Proteins