June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
Sigma 1 Receptor (Sig1R) activation attenuates vasculopathy associated with Retinopathy of Prematurity (ROP)
Author Affiliations & Notes
  • Jing Wang
    Cellular Biology and Anatomy, Augusta University, Augusta, Georgia, United States
    James and Jean Culver Vision Discovery Institute, Augusta University, Augusta, Georgia, United States
  • Haiyan Xiao
    Cellular Biology and Anatomy, Augusta University, Augusta, Georgia, United States
    James and Jean Culver Vision Discovery Institute, Augusta University, Augusta, Georgia, United States
  • zhimin Xu
    James and Jean Culver Vision Discovery Institute, Augusta University, Augusta, Georgia, United States
    Vascular Biology Center, Augusta University, Augusta, Georgia, United States
  • Ruth B Caldwell
    Cellular Biology and Anatomy, Augusta University, Augusta, Georgia, United States
    James and Jean Culver Vision Discovery Institute, Augusta University, Augusta, Georgia, United States
  • Sylvia B Smith
    Cellular Biology and Anatomy, Augusta University, Augusta, Georgia, United States
    James and Jean Culver Vision Discovery Institute, Augusta University, Augusta, Georgia, United States
  • Footnotes
    Commercial Relationships   Jing Wang None; Haiyan Xiao None; zhimin Xu None; Ruth Caldwell None; Sylvia Smith None
  • Footnotes
    Support  Knights Templar Eye Foundation 2020-2022
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 784 – F0343. doi:
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    • Get Citation

      Jing Wang, Haiyan Xiao, zhimin Xu, Ruth B Caldwell, Sylvia B Smith; Sigma 1 Receptor (Sig1R) activation attenuates vasculopathy associated with Retinopathy of Prematurity (ROP). Invest. Ophthalmol. Vis. Sci. 2022;63(7):784 – F0343.

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

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Abstract

Purpose : ROP, a retinal neurovasculopathy, is a leading cause of childhood blindness. We reported recently that activation of the molecular chaperone, Sig1R, provides a novel rescue of neuronal deficits in the oxygen-induced retinopathy (OIR), model of ROP (Wang et al, ARVO 2020). Here, we focus on Sig1R and its novel therapeutic potential in vascular injury characteristic of ROP.

Methods : C57BL/6J pups (P7 with nursing dam) were subjected to OIR or room air (CT). (+)-Pentazocine ((+)-PTZ), a high affinity Sig1R ligand, was administered starting P7 (0.5 mg/kg, IP, every other day). Retinal vasculature was imaged by fluorescein angiography & vascular tortuosity analyzed by MATLAB at P17& P48. At P17, retinal vascular distribution (neovascularization (NV) and avascular area) & vascular barrier function (Evans blue (EB) leakage assay) were evaluated. Oxidative stress (DHE, 3-NT, 4-HNE), reactive gliosis (anti-GFAP), expression of proteins/cytokines (Sig1R, ZO-1, Occludin, p-STAT3 and VEGF, IL-6, TNFα) were assessed by immunohistochemistry (IMH), Dot/Western blotting (WB) & ELISA.

Results : Vascular tortuosity: Retinal arteries in OIR mice were more tortuous (~1.3) v. CT (1.0), whereas (+)-PTZ significantly reduced arterial tortuosity (~1.1) in OIR mice at P17 & P48. Vascular distribution: Retinal avascular region (OIR-non: ~30% v. OIR+PTZ: ~12%) and NV (OIR-non: ~7.8% v. OIR+PTZ: ~2.5%) were significantly decreased in OIR+PTZ mice. Retinal vascular barrier: EB extravasation was elevated in OIR mice, but decreased significantly in OIR+PTZ mice. ZO-1 & Occludin levels decreased significantly in OIR mice, whereas (+)-PTZ preserved their levels. Oxidative stress and reactive gliosis: Detection of oxidative stress by DHE staining, 4-HNE and 3-NT immunostaining showed that (+)-PTZ attenuated superoxide and lipid peroxide levels in OIR mice. (+)-PTZ treatment diminished reactive gliosis in OIR mice. Exploration of Sig1R-STAT3-Inflammation axis. In OIR mice, we observed a significant decrease of Sig1R, along with increase of p-STAT3, VEGF, IL-6 and TNFα, whereas (+)-PTZ treatment normalized these effects.

Conclusions : (+)-PTZ treatment attenuated OIR-induced vasculopathy, retinal barrier dysfunction, reactive gliosis, oxidative stress and STAT3-mediated inflammation, suggesting that Sig1R is a promising therapeutic target for vascular injury in ROP.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

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