Purposes: Ischemic retinopathies are characterized by hypoxia-driven inflammation and pathological neovascularization (NV), with vascular endothelial growth factor (VEGF) as a central mediator. Incomplete responses to anti-VEGF therapy suggest involvement of additional hypoxia-regulated pathways. This study investigated the contribution of stromal cell–derived factor-1 (SDF-1) to VEGF-driven retinal vascular pathology. Methods: SDF-1 expression, leukostasis, vascular nonperfusion (NP), and NV were assessed in oxygen-induced retinopathy, VEGF transgenic mice, and VEGF-injected mice. The SDF-1 aptamer NOX-A12 was administered alone or in combination with aflibercept. Retinal vascular pathology was quantified by immunofluorescence, and vitreous albumin levels were measured to assess vascular leakage. RNA sequencing was performed in VEGF-stimulated human umbilical vein endothelial cells treated with SDF-1. Results: SDF-1 expression was increased in ischemic retinas and in models of sustained VEGF overexpression (Rho P35, 2.43 ± 1.34; Tet/Opsin/VEGF (TVOP), 0.27 ± 0.31; C57 VEGF, 0.13 ± 0.14; retinopathy of prematurity, 3.06 ± 0.65; P = 0.0004, 0.0005, < 0.0001, <0.0001). SDF-1 aptamer plus aflibercept more effectively suppressed retinal leukostasis (24 h, 84.2 ± 13.8 vs 122.2 ± 20.8; 72 h, 22 ± 10.5 vs 52.6 ± 13.1; Rho/VEGF P21, 20.2 ± 7.79 vs 37.4 ± 9.07; Rho/VEGF P35, 20.8 ± 7.63 vs 39.7 ± 8.83; TVOP, 35.3 ± 9.16 vs 170.6 ± 40.9, all P < 0.0001), NP area (80.92 ± 3.82 vs 51.53 ± 11.13; P < 0.0001), hypoxia (0.23 ± 0.10 vs 0.82 ± 0.09; P < 0.0001), and NV (0.01 ± 0.01 vs 0.07 ± 0.01; P < 0.0001) than aflibercept alone, without additional effects on choroidal NV or vitreous albumin levels. Transcriptomic analysis revealed enrichment of pathways related to leukocyte transendothelial migration, focal adhesion, tight junctions, and extracellular matrix organization. Conclusion: SDF-1 functions as a cooperative mediator of VEGF-driven retinal vascular pathology. Dual targeting of SDF-1 and VEGF enhances suppression of ischemic retinal injury and NV.
Ye et al. (Fri,) studied this question.