Platelet Factor-4 Variant: a Novel Angiostatic Chemokine Inhibits Pathological Retinal Neovascularization in Oxygen-Induced Retinopathy Mouse Model

Abstract

Purpose: Recent studies illustrated that the human CXC chemokine platelet factor-4 variant (PF-4var/CXCL4L1) is a more potent angiostatic agent than PF-4 (CXCL4) in inhibiting angiogenesis and tumor growth. PF-4var is angiostatic through interfering with angiogenic growth factors such as VEGF and bFGF and activation of its receptor CXCR3. The goal of this study was to investigate the change in the retinal levels of PF-4 during murine ischemic retinopathy and to test the effect of PF-4var administration on pathological retinal neovascularization (RNV).

Methods: The Oxygen-Induced Retinopathy (OIR) mouse model was used to assess endogenous PF-4 expression and to examine the effect of exogenous PF-4var on RNV. PF-4var (50 ng/eye) was delivered via intraocular injection at postnatal day 12 (p12). Western blot and immunofluorescence were used to assess PF-4 and CXCR3 expression in p14 and p17 retinas and in human retinal endothelial cells (HREC) exposed to hypoxia (O2<0.2%-10Hrs).

Results: Our results illustrated that PF-4 expression in control mice was higher at p17 compared to p14. OIR caused significant increases in PF-4 that peaked at p17 compared to the control. However, we did not detect any change in CXCR3 expression between different groups. On the other hand, HREC exposed to hypoxia showed increases in both PF-4 and CXCR3. Immunofluorescence studies confirmed enhanced PF-4 expression that colocalized with endothelial cells. Finally, injection of PF-4var significantly reduced the pathological RNV in the OIR model.

Conclusions: Our results suggest PF-4var as a novel therapeutic intervention to treat pathological RNV during ischemic retinopathy. Further studies are needed to investigate the underlying mechanisms behind the PF-4var angiostatic effect in RNV

Keywords: 700 retinal neovascularization • 548 hypoxia • 557 inflammation