Transforming Growth Factor beta-Activated Kinase 1 (TAK1) is a novel target for retinal neovascularization

Abstract

Purpose : Therapeutic proteins that suppress Vascular Endothelial Growth Factor (VEGF) and inhibit retinal neovascularization are not effective in all patients, implicating other factors in the pathogenesis of retinal neovascularization. Using a rat model of oxygen-induced retinopathy (OIR), we sought to identify novel therapeutic targets for retinal neovascularization.

Methods : MicroRNA sequencing was performed with retinal RNA isolated from control (normoxic) and rats subjected to OIR. Bioinformatic analysis was undertaken to identify candidate pathways and genes involved in retinal neovascularization, and candidate genes were validated by RT-qPCR. The Transforming Growth Factor beta-Activated Kinase 1 (TAK1) was highly expressed in OIR rats compared with controls. The selective TAK1 inhibitor, 5Z-7-Oxozeaenol (Oxo), was used in in vitro angiogenesis assays to assess its effects on vascular endothelial cell proliferation, migration and tube formation. Oxo and its vehicle as a control were administered intravitreally on postnatal day 14 (P14) in OIR rats.

Results : TAK1 was identified through bioinformatic analysis as a potential target and was up-regulated in the retina of OIR rats. Human endothelial cells treated with Oxo (1µM) showed significant reductions in lumen formation (40.2% reduction, p< 0.001) and branching (56.2% reduction, p<0.001) as well as in migration in the scratch migration assay (63.2% reduction, p<0.001) relative to those treated with vehicle alone. Oxo also suppressed vascular sprouting from mouse aortic ring explants (45.8% reduction, p<0.001) relative to those treated with vehicle alone. In the OIR rat model, there was a significant reduction in retinal neovascularization in eyes that had received either low (18ng) or high dose (90ng) Oxo (50.0% and 53.3% reduction, respectively, p<0.001), compared with vehicle (Figure 1).

Conclusions : These data suggest that TAK1 is involved in development of retinal neovascularization. TAK1 may represent a suitable target for the development of new therapeutics for retinal neovascularization in diseases such as proliferative diabetic retinopathy.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

 

Figure 1. Oxo suppressed retinal neovascularization in vivo. Retinal neovascularization is highlighted in white. ****P<0.0001.