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Peter Westenskow, Toshihide Kurihara, Edith Aguilar, Mariah Webb, Carli Wittgrove, Stacey Moreno, Martin Friedlander; Inhibiting the Ras Pathway Prevents Ocular Neovascularization by Repressing Tip Cell Sprouting. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4535.
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Vascular networks develop from sprouting endothelial tip cells that respond to pro-angiogenic cytokines; inhibiting sprouting may prevent neovascularization in patients with blinding neovascular eye diseases including diabetic retinopathy and age-related macular degeneration. Vascular endothelial growth factor (VEGF) antagonism is effective for some patients but can elicit off-target effects. Novel treatments for neovascularization that circumvent these problems may be developed only as more regulatory pathways that control fundamental angiogenesis events are better understood or identified. In this study we examined the role of Ras signaling in tip cell sprouting.
The expression patterns of pERK and the endogenous Ras inhibitor RasGAP were investigated using in situ hybridization, RT-PCR, and immunohistochemistry in developing retinas and in animal models of neovascularization including oxygen-induced retinopathy (OIR) mice and very low density lipoprotein receptor knockout mice (VLDLR-/-). RasGAP expression was experimentally modulated using anti-miR-132 in OIR, VLDLR-/-, and laser-induced choroidal neovascularization murine models. The effects were quantified using established methods and compared with VEGF-trap.
pERK, a molecular read-out of Ras activation, was detected at high levels in sprouting tip cells in developing and pathological vascular networks while RasGAP is expressed predominately in non-sprouting tip cells and quiescent VEGF insensitive phalanx cells. RasGAP is also ectopically downregulated in multiple neovascular models. Experimental delivery of α-miR-132 inhibits Ras signaling and prevents neovascularization in all the models examined even more potently than VEGF-trap.
Here we report that the Ras pathway, which functions downstream of a wide range of cytokines including VEGF, is active in sprouting tip cells and can be modulated using microRNA-based therapies to prevent neovascularization. This novel therapeutic strategy may prove useful for treating multiple neovascular diseases of the eye and for preventing vision loss regardless of the neovascular stimulus.
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