Activation of Endothelial Ras Signaling Bypasses Senescence and Causes Abnormal Vascular Morphogenesis

Angiogenesis is crucial for embryogenesis, reproduction, and wound healing and is a critical determinant of tumor growth and metastasis. The multifunctional signal transducer Ras is a proto-oncogene and frequently becomes mutated in a variety of human cancers, including angiosarcomas. Regulation of Ras is important for endothelial cell function and angiogenesis. Hyperactivation of Ras is linked with oncogene-induced senescence in many cell types. Given links between vascular malformations and angiosarcoma with activated Ras signaling, we sought to determine the consequence of sustained Ras activation on endothelial cell function. We find that sustained Ras activation in primary endothelial cells leads to prolonged activation of progrowth signaling, accompanied by a senescence bypass, enhanced proliferation, autonomous growth, and increased survival. Moreover, Ras severely compromises the ability of these cells to organize into vascular structures, instead promoting formation of planar endothelial sheets. This abnormal phenotype is regulated by phosphoinositide 3-kinase signaling, highlighting the therapeutic potential of agents targeting this axis in dealing with vascular morphogenic disorders and vascular normalization of tumors.