July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
Targeting neurovascular injury: Arginase 1 promotes angiogenic repair and limits neurodegeneration
Author Affiliations & Notes
  • Ruth B Caldwell
    Vascular Biology Center, Medical College of Georgia, Augusta, Georgia, United States
    Charlie Norwood VA Medical Center, Augusta, Georgia, United States
  • Abdelrahman Y Fouda
    Vascular Biology Center, Medical College of Georgia, Augusta, Georgia, United States
    Vision Discovery Institute, Medical College of Georgia, Georgia, United States
  • Zhimin Xu
    Vascular Biology Center, Medical College of Georgia, Augusta, Georgia, United States
    Vision Discovery Institute, Medical College of Georgia, Georgia, United States
  • Jutamas Suwanpradid
    Vascular Biology Center, Medical College of Georgia, Augusta, Georgia, United States
  • Modesto Rojas
    Vascular Biology Center, Medical College of Georgia, Augusta, Georgia, United States
    Vision Discovery Institute, Medical College of Georgia, Georgia, United States
  • Esraa Shosha
    Vascular Biology Center, Medical College of Georgia, Augusta, Georgia, United States
    Vision Discovery Institute, Medical College of Georgia, Georgia, United States
  • Chintan Patel
    Vascular Biology Center, Medical College of Georgia, Augusta, Georgia, United States
  • Ji Xing
    Vascular Biology Center, Medical College of Georgia, Augusta, Georgia, United States
  • S. Priya Narayanan
    Clinical Pharmacy, University of Georgia, Georgia, United States
    Vision Discovery Institute, Medical College of Georgia, Georgia, United States
  • Robert W. Caldwell
    Pharmacology & Toxicology, Medical College of Georgia, Augusta, Georgia, United States
    Vision Discovery Institute, Medical College of Georgia, Georgia, United States
  • Footnotes
    Commercial Relationships   Ruth Caldwell, None; Abdelrahman Fouda, None; Zhimin Xu, None; Jutamas Suwanpradid, None; Modesto Rojas, None; Esraa Shosha, None; Chintan Patel, None; Ji Xing, None; S. Priya Narayanan, None; Robert Caldwell, None
  • Footnotes
    Support  NIH Grant EY11766, VA Grant BX001233, AHA Postdoctoral Fellowship Grant 18POST34060036
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 3258. doi:https://doi.org/
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      Ruth B Caldwell, Abdelrahman Y Fouda, Zhimin Xu, Jutamas Suwanpradid, Modesto Rojas, Esraa Shosha, Chintan Patel, Ji Xing, S. Priya Narayanan, Robert W. Caldwell; Targeting neurovascular injury: Arginase 1 promotes angiogenic repair and limits neurodegeneration. Invest. Ophthalmol. Vis. Sci. 2019;60(9):3258. doi: https://doi.org/.

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

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Abstract

Purpose : The lack of therapies to limit injury and promote repair during retinopathy of prematurity (ROP) and other ischemic retinopathies is a major clinical problem. We have discovered that deleting the mitochondrial isoform of the ureohydrolase arginase (A) enzyme A2 reduces both vascular and neuronal injury in the oxygen-induced retinopathy (OIR) model of ROP whereas the cytosolic isoform A1 is neuroprotective in a model of ischemia/reperfusion injury. Here, we examined the role of A1 in OIR.

Methods : Studies were performed using knockout (KO) mice lacking one copy of A1 (A1+/-), wild type (WT) littermates, and WT mice injected intravitreally with the investigational drug PEGylated A1 (PEG-A1, 6.8 ng in 0.5 µL) or vehicle (PBS). For studies in KO mice, neonatal A1+/- and littermate control mice (P7) were maintained in 70% oxygen for 2-5 days, transferred to room air, and sacrificed at various times. For PEG-A1 studies, WT pups were injected intravitreally with PEG-A1 (or vehicle) on P7, maintained in 75% oxygen for 2 days, and sacrificed on P9 for analysis vaso-obliteration. Another cohort of WT pups was maintained in 75% oxygen from P7 to P12, injected intravitreally with PEG-A1 (or vehicle) on P12, and sacrificed on P17. Vaso-obliteration, neovascularization, and neuronal survival were quantified by image analysis of immuno-labeled retina flat mounts and tissue sections.

Results : Neither A1 deletion (n=4-8) nor PEG-A1 treatment (n=13-17) altered hyperoxia-induced vaso-obliteration as compared with the WT or vehicle controls (p>0.05). However, A1 deletion was associated with a decrease in physiologic revascularization of the OIR retinas at P17 (p<0.05, n=7-11), whereas PEG-A1 treatment promoted angiogenic repair as shown by increases in vascular sprouting and tip cell formation (p<0.05, n=4-5), and decreases in the avascular area (p<0.05, n=18). PEG-A1 treatment also prevented OIR-induced neuronal loss as measured by preservation of calbindin-positive horizontal cells (p<0.05, n=6) and decreased levels of the apoptotic marker cleaved PARP (p<0.05, n=3-4). Furthermore, PEG-A1 treatment promoted an increase in infiltration of Iba1-positive macrophage/microglia that were also positive for A1.

Conclusions : PEG-A1 enhances reparative angiogenesis and promotes neuronal survival in OIR. PEG-A1 may offer a novel therapy for limiting neurovascular injury during ROP and other forms of ischemic retinopathy.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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