FGF21 Administration Suppresses Retinal and Choroidal Neovascularization in Mice

Abstract

Summary Pathological neovascularization, a leading cause of blindness, is seen in retinopathy of prematurity, diabetic retinopathy and age related macular degeneration. Using a mouse model of hypoxia-driven retinal neovascularization we find that fibroblast growth factor 21 (FGF21) administration suppresses, and FGF21 deficiency worsens, retinal neovessel growth. The protective effect of FGF21 against neovessel growth was abolished in adiponectin (APN)-deficient mice. FGF21 administration also decreased neovascular lesions in two models of neovascular age-related macular degeneration, very-low-density-lipoproteinreceptor- deficient mice with retinal angiomatous proliferation and laser-induced choroidal neovascularization. FGF21 inhibited TNFα expression but did not alter Vegfa expression in neovascular eyes. These data suggest that FGF21 may be a therapeutic target for pathologic vessel growth in patients with neovascular eye diseases including retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration.

Fibroblast Growth Factor 21 Protects Photoreceptor Function in Type 1 Diabetic Mice

“…We also found that PF-05231023 protection against retinal neuronal deficits was preserved with APN deficiency. In the OIR mouse model of late vasoproliferative retinopathy, FGF21 inhibits pathological neovessel growth mediated by APN (17). Our current findings indicate that FGF21 regulates retinal neuron and neovessel growth through other mechanisms.…”

“…Additionally, PF-05231023induced effect on IL-1b was independent of APN in diabetic retinas, which is in line with the neuronal observation. APN inhibits retinal neovessel growth via tumor necrosis factor-a (TNF-a) (59), and FGF21 also reduces TNF-a in neovascular mouse retinas (17). However, in Akita mice, there was no significant change in retinal Tnfa expression between PF-05231023-and vehicle-treated groups.…”

“…NRF2 upregulates antioxidant enzyme expression and is a critical defense mechanism against oxidative stress in the retina (16). We previously found that FGF21 decreases pathological retinal vessel proliferation and promotes physiological retinal vascularization in mouse oxygen-induced retinopathy (OIR), modeling late proliferative DR (17). However, there is limited knowledge of the role of FGF21 in early DR. We investigated whether FGF21 protection against early retinal neuronal dysfunction in diabetes in the following two mouse models of type 1 diabetes: 1) insulin-deficient Akita mice; and 2) streptozotocin (STZ)-induced diabetic mice.…”

Homocysteine Facilitates Prominent Polygonal Angiogenetic Networks of a Choroidal Capillary Sprouting Model

“…This model provided an ideal tool for investigating choroidal capillary sprouting, which was not observed in the animal model in vivo. 22 This effect was also observed when the concentration of hcy was increased to 2 mM, but the sprouting area was not as large as that obtained with 1-mM hcy after 120 hours of culture. Hcy has been reported to be cytotoxic through the upregulation of Fas receptor expression, which leads to cell apoptosis in human umbilical vein endothelial cells cultured with 5-mM hcy.…”

Dyslipidemia in retinal metabolic disorders

“…FGF21 also regulates adiponectin (APN) production and secretion, and APN is key in mediating FGF21 modulation of glucose and lipid metabolism in mice (Holland et al , ; Lin et al , ). FGF21, mediated by APN which is associated with a number of metabolic retinal disorders (Fu et al , 2016), inhibits ocular neovascularization in mice (Fu et al , ). FGF21 also increases APN secretion to diminish accumulation of ceramides in obese animals (Holland et al , ).…”