Co-operative Activities of VEGF and SDF-1 in Retina

Abstract

Purpose : Previous studies have shown that stromal-derived factor-1 (SDF-1) is increased in ischemic retina and contributes to ischemia-induced retinal neovascularization (NV); however vascular endothelial growth factor (VEGF) is the major contributor and it is not known whether SDF-1 and VEGF act independently or co-operatively. In this study we sought to address that experimental question.

Methods : An aptamer that specifically neutralizes SDF-1 (AMS0603) was used to investigate the effect of SDF-1 in oxygen-induced ischemic retinopathy (OIR), rho/VEGF and Tet/opsin/VEGF mice with over-expression of VEGF in the retina, and in wild type mice given an intraocular injection of 200ng of VEGF.

Results : Compared with untreated mice, retinal sdf1 mRNA was not increased 24 hours after intraocular injection of VEGF but was elevated after increased expression of VEGF in Tet/opsin/VEGF mice (3 days) or P35 rho/VEGF mice (3 weeks). There was leukostasis 24 and 72 hours after injection of 200ng of VEGF that was significantly reduced by pre-injection of 20µg of AMS0603 (24h, 84.2±13.8 vs 122.2±20.8, p=0.0238; 72h, 22±10.5 vs 52.6±13.1, p=0.0087) after injection of VEGF. Injection of 20µg of AMS0603 also reduced leukostasis in rho/VEGF mice at P21 (20.2±7.79 vs 37.4±9.07, p=0.0317) and P35 (20.8±7.63 vs 39.7±8.83, p=0.0001) and in Tet/opsin/VEGF mice (35.3±9.16 vs 170.6±40.9, p=0.0043). Injection of 20µg of AMS0603 + 20µg of aflibercept caused greater reduction of retinal NV in OIR than either alone, but there was no additive effect for suppression of choroidal NV at Bruch’s membrane rupture sites.

Conclusions : Prolonged over-expression of VEGF in retina increases levels of SDF-1 which contributes to VEGF-induced leukostasis. There is added benefit from combined suppression of VEGF and SDF-1 for treatment of retinal NV in ischemic retinopathy, but not for treatment of choroidal NV.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.