Fibroblast growth factor 21 protects against phase I retinopathy of prematurity

Abstract

Purpose : The primary cause of retinopathy of prematurity (ROP) is delayed retinal vascularization of immature retinas after preterm birth (phase I ROP). Neonatal metabolic dysfunction (hyperglycemia and dyslipidemia) occurring in the first few weeks of life is a very important but understudied (and potentially treatable) risk factor for phase I ROP. In term infants, blood fibroblast growth factor 21 (FGF21) levels increase beginning 2 days after birth and FGF21 levels positively correlate with postnatal growth. However, in preterm infants, FGF21 levels are very low, detectable in only 69% of preterm infants at postnatal week 1. We investigated if FGF21 promotes retinal vessel growth in phase I ROP utilizing a recently developed phase I ROP mouse model.

Methods : Neonatal metabolic dysfunction was induced with intraperitoneal (i.p.) injection of streptozotocin in mice from postnatal (P) day 1 to 9. At P10, retinal vessel growth was evaluated in FGF21- (i.p. from P7 to P9) vs vehicle-treated C57BL/6J (n=14-16), FGF21-knockout vs FGF21 wild-type mice (n=15-22). Co-treatment of FGF21 with intravitreal siRNA Acaca (the key enzyme in de novo fatty acid synthesis) or control (n=8-9), or i.p. etomoxir (CPT1A inhibitor) or control (n=8-9) in C57BL/6J mice was also conducted. Retinal metabolic enzyme levels were measured with quantitative proteomics and retinal lipid levels were analyzed with lipidomics. Both male and female mice were used. Littermate controls were used for drug treatment. Unpaired t test was used for statistical analysis.

Results : In mice modeling phase I ROP, FGF21 administration promoted (P<0.001) and FGF21 deficiency (P<0.01) worsened retinal vessel growth. Blocking retinal Acaca expression partially attenuated (P<0.05), while inhibiting CPT1A with etomoxir greatly decreased (P<0.01) FGF21 protection in retinal vessel growth. FGF21 did not change the protein levels of retinal metabolic enzymes. FGF21 reduced retinal lipid levels.

Conclusions : FGF21 protects against retinal vascular developmental delay in phase I ROP, possibly through modulating retinal lipid metabolism.

This is a 2021 ARVO Annual Meeting abstract.