Ras pathway inhibition prevents neovascularization by repressing endothelial cell sprouting

Peter D. Westenskow, Toshihide Kurihara, Edith Aguilar, Elizabeth L. Scheppke, Stacey K. Moreno, Carli Wittgrove, Valentina Marchetti, Iacovos P. Michael, Sudarshan Anand, Andras Nagy, David Cheresh, Martin Friedlander

Research output: Contribution to journalArticle

43 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)4900-4908
Number of pages9
JournalJournal of Clinical Investigation
Volume123
Issue number11
DOIs
StatePublished - Nov 1 2013
Externally publishedYes

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Vascular Endothelial Growth Factor A
Endothelial Cells
Blood Vessels
p120 GTPase Activating Protein
Eye Diseases
MicroRNAs
Macular Degeneration
Cues
Rodentia
Down-Regulation
Inhibition (Psychology)
Cytokines
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Westenskow, P. D., Kurihara, T., Aguilar, E., Scheppke, E. L., Moreno, S. K., Wittgrove, C., ... Friedlander, M. (2013). Ras pathway inhibition prevents neovascularization by repressing endothelial cell sprouting. Journal of Clinical Investigation, 123(11), 4900-4908. https://doi.org/10.1172/JCI70230

Ras pathway inhibition prevents neovascularization by repressing endothelial cell sprouting. / Westenskow, Peter D.; Kurihara, Toshihide; Aguilar, Edith; Scheppke, Elizabeth L.; Moreno, Stacey K.; Wittgrove, Carli; Marchetti, Valentina; Michael, Iacovos P.; Anand, Sudarshan; Nagy, Andras; Cheresh, David; Friedlander, Martin.

In: Journal of Clinical Investigation, Vol. 123, No. 11, 01.11.2013, p. 4900-4908.

Research output: Contribution to journalArticle

Westenskow, PD, Kurihara, T, Aguilar, E, Scheppke, EL, Moreno, SK, Wittgrove, C, Marchetti, V, Michael, IP, Anand, S, Nagy, A, Cheresh, D & Friedlander, M 2013, 'Ras pathway inhibition prevents neovascularization by repressing endothelial cell sprouting', Journal of Clinical Investigation, vol. 123, no. 11, pp. 4900-4908. https://doi.org/10.1172/JCI70230
Westenskow PD, Kurihara T, Aguilar E, Scheppke EL, Moreno SK, Wittgrove C et al. Ras pathway inhibition prevents neovascularization by repressing endothelial cell sprouting. Journal of Clinical Investigation. 2013 Nov 1;123(11):4900-4908. https://doi.org/10.1172/JCI70230
Westenskow, Peter D. ; Kurihara, Toshihide ; Aguilar, Edith ; Scheppke, Elizabeth L. ; Moreno, Stacey K. ; Wittgrove, Carli ; Marchetti, Valentina ; Michael, Iacovos P. ; Anand, Sudarshan ; Nagy, Andras ; Cheresh, David ; Friedlander, Martin. / Ras pathway inhibition prevents neovascularization by repressing endothelial cell sprouting. In: Journal of Clinical Investigation. 2013 ; Vol. 123, No. 11. pp. 4900-4908.
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