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Leo A Kim, Jonathan D. Lam, Angie Sanchez, Dhanesh Amarnani, Jonathan Cardona-Velez, Joseph Arboleda-Velasquez; Inhibition of Runx1 by the Ro5-3335 benzodiazepine derivative reduces aberrant retinal angiogenesis. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4029.
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© ARVO (1962-2015); The Authors (2016-present)
Runx1, the runt-related transcription factor 1, has been implicated in endothelial cell function. We recently identified Runx1 expression to be enhanced in endothelial cells isolated from fibrovascular membranes of patients with proliferative diabetic retinopathy. Ro5-3335 is a well characterized inhibitor of Runx1 function in models of leukemia. We hypothesize that inhibition of Runx1 function, with the Ro5-3335 inhibitor, may ameliorate pathologic retinal neovascularization.
The oxygen-induced retinopathy model of retinal angiogenesis was employed for this study. Wild-type C57BL/6J P7 mice were exposed to 75% O2 for 5 days and returned to room air (P12). Mice were treated with 75 μM Ro5-3335 inhibitor (n = 7) or DMSO vehicle (n = 7) via intravitreal injections in the left eye at P13 and P15 before sample collection at P17. Retina were dissected and stained for Isolectin B4, CD31, and Runx1 followed by quantification of the vaso-obliterative and neovascular regions.
Untreated eyes stained for Runx1 and Isolectin B4 demonstrate selective staining of neovascular tufts for Runx1. There was significant reduction in neovascular tuft area in the inhibitor treated group (5.2% ± 2.2 whole retina) compared to vehicle (10.4% ± 3.0 whole retina, p=0.003). The vaso-obliterative region of the inhibitor treated group (9.9% ± 4.7 whole retina) was comparable to the vehicle treated group (14.2% ± 5.9 whole retina, p=0.16).
The localization of Runx1 staining to neovascular tufts suggests it is a novel and specific regulator of endothelial cell function in aberrant retinal angiogenesis. Intravitreal injection of Ro5-3335 was associated with a significant decrease in neovascular tuft area compared to vehicle treated pups. This was not associated with a significant shift in the avascular region suggesting independent regulation between normal and abnormal vascularization of the retina. Inhibition of Runx1 function with Ro5-3335 is efficacious in reducing pathologic retinal neovascularization.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
Quantification of vaso-obliteration and neovascularization at P17 in a mouse model of oxygen induced retinopathy. Animals were injected with vehicle (DMSO) control (Top Row) or with 75 μM Ro5-3335 (Bottom Row). Retina were stained for CD31 (First Column), and the area of vaso-obliteration (Second Column) and neovascularization (Third Column) quantified.
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