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.
Sanford-Burnham Medical Research Institute at Lake Nona, Orlando, FL 32827, USA.
Junko
J
Sawada
Takeo
T
Urakami
Fangfei
F
Li
Akane
A
Urakami
Weiquan
W
Zhu
Minoru
M
Fukuda
Dean Y
DY
Li
Erkki
E
Ruoslahti
Masanobu
M
Komatsu
D022005:Adherens Junctions / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001808:Blood Vessels / Q000002:abnormalities / Q000254:growth & development / Q000378:metabolism / Q000503:physiopathology*; D015820:Cadherins / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004705:Endocytosis / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D051379:Mice; D008954:Models, Biological; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism*; D009024:Morphogenesis / Q000187:drug effects; D009369:Neoplasms / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000503:physiopathology*; D020286:Pericytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011393:Procollagen-Proline Dioxygenase; D012038:Regeneration / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D018631:ras Proteins / Q000172:deficiency / Q000378:metabolism*; D000099152:Cadherin 5; D000099162:Endothelial PAS Domain-Containing Protein 1
D015703:Antigens, CD; D051792:Basic Helix-Loop-Helix Proteins; D015820:Cadherins; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D020559:Monomeric GTP-Binding Proteins; D011393:Procollagen-Proline Dioxygenase; D042461:Vascular Endothelial Growth Factor A; D018631:ras Proteins; D000099152:Cadherin 5; D000099162:Endothelial PAS Domain-Containing Protein 1; C490189:Egln1 protein, mouse; C085929:RRAS protein, human; C513254:Rras protein, mouse