Abstract
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.
Copyright © 2012 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adherens Junctions / drug effects
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Adherens Junctions / metabolism
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Animals
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Antigens, CD / metabolism
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Blood Vessels / abnormalities
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Blood Vessels / growth & development
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Blood Vessels / metabolism
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Blood Vessels / physiopathology*
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Cadherins / metabolism
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Cell Hypoxia / drug effects
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Down-Regulation / drug effects
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Endocytosis / drug effects
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Endothelial Cells / drug effects
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Endothelial Cells / metabolism
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Humans
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Hypoxia-Inducible Factor-Proline Dioxygenases
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Mice
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Models, Biological
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Monomeric GTP-Binding Proteins / metabolism*
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Morphogenesis / drug effects
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Neoplasms / blood supply*
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Neoplasms / metabolism*
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Neoplasms / pathology
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Neovascularization, Pathologic / metabolism
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Neovascularization, Pathologic / physiopathology*
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Pericytes / drug effects
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Pericytes / metabolism
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Pericytes / pathology
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Phenotype
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Procollagen-Proline Dioxygenase
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Regeneration / drug effects
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Signal Transduction / drug effects
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Up-Regulation / drug effects
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Vascular Endothelial Growth Factor A / pharmacology
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ras Proteins / deficiency
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ras Proteins / metabolism*
Substances
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Antigens, CD
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Basic Helix-Loop-Helix Transcription Factors
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Cadherins
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Vascular Endothelial Growth Factor A
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cadherin 5
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endothelial PAS domain-containing protein 1
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Procollagen-Proline Dioxygenase
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Egln1 protein, mouse
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Hypoxia-Inducible Factor-Proline Dioxygenases
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RRAS protein, human
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Rras protein, mouse
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Monomeric GTP-Binding Proteins
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ras Proteins