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Ras pathway inhibition prevents neovascularization by repressing endothelial cell sprouting

Academic Article
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Overview

authors

  • Westenskow, Peter
  • Kurihara, Toshihide
  • Aguilar, E.
  • Scheppke, E. L.
  • Moreno, S. K.
  • Wittgrove, C.
  • Marchetti, V.
  • Michael, I. R.
  • Anand, S.
  • Nagy, A.
  • Cheresh, D.
  • Friedlander, Martin

publication date

  • November 2013

journal

  • Journal of Clinical Investigation  Journal

abstract

  • Vascular networks develop from a growing vascular front that responds to VEGF and other guidance cues. Angiogenesis is required for normal tissue function, but, under conditions of stress, inappropriate vascularization can lead to disease. Therefore, inhibition of angiogenic sprouting may prevent neovascularization in patients with blinding neovascular eye diseases, including macular degeneration. VEGF antagonists have therapeutic benefits but also can elicit off-target effects. Here, we found that the Ras pathway, which functions downstream of a wide range of cytokines including VEGF, is active in the growing vascular front of developing and pathological vascular networks. The endogenous Ras inhibitor p120RasGAP was expressed predominately in quiescent VEGF-insensitive endothelial cells and was ectopically downregulated in multiple neovascular models. MicroRNA-132 negatively regulated p120RasGAP expression. Experimental delivery of α-miR-132 to developing mouse eyes disrupted tip cell Ras activity and prevented angiogenic sprouting. This strategy prevented ocular neovascularization in multiple rodent models even more potently than the VEGF antagonist, VEGF-trap. Targeting microRNA-132 as a therapeutic strategy may prove useful for treating multiple neovascular diseases of the eye and for preventing vision loss regardless of the neovascular stimulus.

subject areas

  • Animals
  • Disease Models, Animal
  • Endothelial Cells
  • Humans
  • MAP Kinase Signaling System
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • MicroRNAs
  • Neovascularization, Pathologic
  • Neovascularization, Physiologic
  • Receptors, LDL
  • Retinal Neovascularization
  • Retinal Vessels
  • Signal Transduction
  • Vascular Endothelial Growth Factor A
  • p120 GTPase Activating Protein
  • ras Proteins
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Identity

PubMed Central ID

  • PMC3809796

International Standard Serial Number (ISSN)

  • 0021-9738

Digital Object Identifier (DOI)

  • 10.1172/jci70230

PubMed ID

  • 24084735
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Additional Document Info

start page

  • 4900

end page

  • 4908

volume

  • 123

issue

  • 11

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