Fibroblast growth factor 21 administration suppresses pathologic retinal vessel growth in oxygen-induced retinopathy

Abstract

Purpose : Fibroblast growth factor 21 (FGF21), mediated by adiponectin (APN), improves the lipid profile in rodents, non-human primates and obese patients with diabetes. However, it is unknown if FGF21 inhibits complications of diabetes, specifically pathologic retinal neovascularization in diabetic retinopathy. We investigated if FGF21 suppressed retinal neovascularization in a mouse model of oxygen-induced retinopathy (OIR), modeling proliferative diabetic retinopathy.

Methods : To induce OIR, C57BL/6J mouse pups were exposed to 75% oxygen from postnatal day P7-12. Native FGF21 or long-acting FGF21, PF-05231023, or vehicle was injected intraperitoneally from P12-16 to littermates and neovascularization evaluated at P17 (n=14-19). Retinal neovascularization was also compared in OIR FGF21 wild-type (Fgf21^+/+) and knockout (Fgf21^-/-) retinas (n=12-13). To examine the direct retinal effect on C57BL/6J OIR mice, P17 neovascularization was compared after P12 intra-vitreal PF-05231023 treatment of one eye and with vehicle treatment of the contralateral eye (n=7). To determine if APN mediates the effects on neovascularization of FGF21 in OIR, PF-05231023 and vehicle was injected i.p. in Apn^-/- mice (n=11-14). Retinal FGF21 receptors, Apn and tumor necrosis factor alpha (Tnfα) levels were examined by qPCR. Both male and female mice were used. All data except low quality images that were insufficient for analysis were used. The percentage of retinal neovascular area over the total retinal area was quantified at P17.

Results : FGF21 administration suppressed (vehicle: 10.8±0.6%; native FGF21: 8.8±0.4%; PF-05231023: 5.4±0.7%) and FGF21 deficiency (Fgf21^+/+: 6.5±0.3%; Fgf21^-/-:7.5±0.3%) worsened pathologic retinal neovascularization. Intravitreal delivery of PF-05231023 directly inhibited neovascularization (vehicle: 6.6±0.8%; PF-05231023: 4.5±0.8%). FGF21 receptors were expressed in mouse retinas and PF-05231023 increased retinal levels of Apn and decreased Tnfα. FGF21 protection against pathologic neovessel growth was completely abolished with APN deficiency (vehicle: 9.2±0.6%; PF-05231023: 8.2±0.6%) and the reduction in retinal Tnfα levels.

Conclusions : Our data suggest that FGF21 inhibits retinal neovascularization through APN pathway activation. FGF21 administration may prevent pathological retinal vascular proliferation in patients with neovascular retinopathy.

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