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

Abstract

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.

Cite this article

Komatsu, M., Ruoslahti, E. R-Ras is a global regulator of vascular regeneration that suppresses intimal hyperplasia and tumor angiogenesis. Nat Med 11, 1346–1350 (2005). https://doi.org/10.1038/nm1324

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