Supplemental Oxygen can Cause Intravitreous Neovascularization through JAK/STAT Pathways in a Model of Retinopathy of Prematurity

¹ Ophthalmology, University of North Carolina, Chapel Hill, North Carolina, United States
² Ophthalmology, University of North Carolina, 103 Mason Farm Road, Chapel Hill, North Carolina, 27599-7041, United States

^* To whom correspondence should be addressed. E-mail: hartnet{at}med.unc.edu.

	Abstract

Purpose: To investigate whether oxygen stresses experienced in retinopathy of prematurity (ROP) would trigger signaling through reactive oxygen species (ROS) and the Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathways to lead to intravitreous neovascularization (IVNV) in an oxygen-induced retinopathy (OIR) rat model. Methods: Newborn rat pups exposed to repeated fluctuations in oxygen and rescued in supplemental oxygen (28% O2, 50/10 OIR+SO) were treated with apocynin, an NADPH oxidase and ROS inhibitor (10 mg/kg/day), AG490, a JAK2 inhibitor (5mg/kg/day), or phosphate buffered saline (PBS). Intraperitoneal injections were given from postnatal day (p)12-p17 (apocynin), or from p3-p17 (AG490). Outcomes were intravitreous neovascularization and avascular/total retinal areas, vascular endothelial growth factor (VEGF), phosphorylated JAK2, and phosphorylated STAT3. Results: Apocynin significantly reduced phosphorylated STAT3 in 50/10 OIR+SO (p=0.04), in association with previously reported inhibition of IVNV area. Inhibition of JAK with AG490 significantly reduced phosphorylated JAK2 (p<0.001), phosphorylated STAT3 (p=0.002), and IVNV area (p=0.033) in the 50/10 OIR+SO model compared to control. Conclusions: Activation of NADPH oxidase from supplemental oxygen works via activated STAT3 to lead to IVNV. In addition, inhibition of the JAK/STAT pathway reduces IVNV. Further studies are needed to determine the effects and relationships of oxygen stresses on JAK/STAT and NAPDH oxidase signaling.

Key Words: angiogenesis, retinopathy of prematurity, JAK/STAT