Small GTPase R-Ras Regulates Integrity and Functionality of Tumor Blood Vessels

We show that R-Ras, a small GTPase of the Ras family, is essential for the establishment of mature, functional blood vessels in tumors. The genetic disruption of R-Ras severely impaired the maturation processes of tumor vessels in mice. Conversely, the gain of function of R-Ras improved vessel structure and blood perfusion and blocked plasma leakage by enhanced endothelial barrier function and pericyte association with nascent blood vessels. Thus, R-Ras promotes normalization of the tumor vasculature. These findings identify R-Ras as a critical regulator of vessel integrity and function during tumor vascularization. [Display omitted] ► Normalization of pathologically regenerating vasculature by a Ras homolog ► A crucial role of R-Ras for endothelial integrity ► R-Ras regulates pericytes and their association with tumor vessels ► A potential O2-sensing independent vascular normalization phenomenon identified