July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
PERK inhibition suppresses pathological retinal neovascularization and promotes physiological retinal vascular repair in a mouse model of oxygen-induced retinopathy
Author Affiliations & Notes
  • Shuang Zhu
    Ophthalmology, The University of Texas Medical Branch, GALVESTON, Texas, United States
  • Hua Liu
    Ophthalmology, The University of Texas Medical Branch, GALVESTON, Texas, United States
    Center for Biomedical Engineering, The University of Texas Medical Branch, GALVESTON, Texas, United States
  • Yonju Ha
    Ophthalmology, The University of Texas Medical Branch, GALVESTON, Texas, United States
  • Wenbo Zhang
    Ophthalmology, The University of Texas Medical Branch, GALVESTON, Texas, United States
    Neuroscience and Cell Biology, The University of Texas Medical Branch, GALVESTON, Texas, United States
  • Footnotes
    Commercial Relationships   Shuang Zhu, None; Hua Liu, None; Yonju Ha, None; Wenbo Zhang, None
  • Footnotes
    Support  NIH grant EY022694, EY026629, AG055771, the John Sealy Memorial Endowment Fund for Biomedical Research, Retina Research Foundation (W.Z.); and American Heart Association 17SDG33630151 (to H.L.).
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 2644. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      Shuang Zhu, Hua Liu, Yonju Ha, Wenbo Zhang; PERK inhibition suppresses pathological retinal neovascularization and promotes physiological retinal vascular repair in a mouse model of oxygen-induced retinopathy. Invest. Ophthalmol. Vis. Sci. 2018;59(9):2644.

      Download citation file:


      © ARVO (1962-2015); The Authors (2016-present)

      ×
  • Supplements
Abstract

Purpose : Retinal neovascularization is a major cause of blindness in ischemic retinopathy including retinopathy of prematurity (ROP) and proliferative diabetic retinopathy. Protein kinase RNA-like endoplasmic reticulum kinase (PERK) is one of branches of the endoplasmic reticulum (ER) stress which can be activated by distinct insults including hypoxia. This study was to investigate the role of PERK in ischemic retinopathy.

Methods : Studies were performed in a mouse model of oxygen-induced retinopathy (OIR) by maintaining wild type mice in 70% oxygen from postnatal day (P)7 to P12 and room air from P12 to P17. GSK2606414, a potent and selective inhibitor targeting PERK, was orally administered (50 mg/kg, once daily) to OIR pups from P12 to P16. Retinas were collected at P17 for analysis of phospho-PERK by Western blot. Whole retinas were labeled with isolectin B4 and the vasculature was examined by fluorescence microscopy.

Results : The level of p-PERK was significantly increased (1.9 fold) in OIR retinas compared to room air control retinas at P17, suggesting that PERK pathway was activated in OIR model. After treatment with GSK2606414, OIR-induced phosphorylation of PERK was blunted in comparison to vehicle treatment, indicating PERK pathway could be effectively blocked by its inhibitor. Importantly, inhibition of PERK manifested a 36% reduction of retinal neovascularization (NV) and a 13% decrease of avascular area (p<0.05) compared to vehicle treatment during OIR. Moreover, in GSK2606414-treated OIR mice, the density and the distribution of the endothelial tip cells was elevated 2.8-fold at the junction of the vascular and avascular retina, and both the number and the length of tip cell filopodia were dramatically increased at P17. Although GSK2606414 treatment did not affect OIR-induced upregulation of angiogenic molecules including VEGF, EPO, Dll4, FGF2 and angiopoietin 2, it markedly reduced upregulation of CD206 and CD86, markers for M2 macrophage/microglia that promotes pathological angiogenesis.

Conclusions : These data indicate that PERK pathway is involved in the development of pathological angiogenesis likely by regulation of M2 macrophage/microglia during retinal ischemia. Pharmacological inhibition of PERK may provide a novel approach to alleviate aberrant retinal vascular formation and promote normal retinal vessel regrowth.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×