June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
Maternal Uteroplacental Insufficiency Protects Offspring from Oxygen-Induced Vascular Loss Through Erythropoietin Receptor Mediated Signaling
Author Affiliations & Notes
  • Thaonhi Hoang Cung
    University of Utah Health John A Moran Eye Center, Salt Lake City, Utah, United States
    Texas Tech University Health Sciences Center School of Medicine, Lubbock, Texas, United States
  • Eric Kunz
    University of Utah Health John A Moran Eye Center, Salt Lake City, Utah, United States
  • Haibo Wang
    University of Utah Health John A Moran Eye Center, Salt Lake City, Utah, United States
  • Aniket Ramshekar
    University of Utah Health John A Moran Eye Center, Salt Lake City, Utah, United States
  • Colin Bretz
    University of Utah Health John A Moran Eye Center, Salt Lake City, Utah, United States
  • Ashley Brown
    University of Utah Health, Salt Lake City, Utah, United States
  • Vladimir Divoky
    Univerzita Palackeho v Olomouci, Olomouc, Olomoucký, Czechia
  • Camille Fung
    University of Utah Health, Salt Lake City, Utah, United States
  • Mary Elizabeth Hartnett
    University of Utah Health John A Moran Eye Center, Salt Lake City, Utah, United States
  • Footnotes
    Commercial Relationships   Thaonhi Cung None; Eric Kunz None; Haibo Wang None; Aniket Ramshekar None; Colin Bretz None; Ashley Brown None; Vladimir Divoky None; Camille Fung None; Mary Elizabeth Hartnett None
  • Footnotes
    Support  National Institutes of Health EY014800; Unrestricted Grant from Research to Prevent Blindness, Inc., New York, NY, to the Department of Ophthalmology & Visual Sciences, University of Utah; National Institutes of Health R01EY015130, R01EY017011
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 4113 – F0350. doi:
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      Thaonhi Hoang Cung, Eric Kunz, Haibo Wang, Aniket Ramshekar, Colin Bretz, Ashley Brown, Vladimir Divoky, Camille Fung, Mary Elizabeth Hartnett; Maternal Uteroplacental Insufficiency Protects Offspring from Oxygen-Induced Vascular Loss Through Erythropoietin Receptor Mediated Signaling. Invest. Ophthalmol. Vis. Sci. 2022;63(7):4113 – F0350.

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

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Abstract

Purpose : Maternal uteroplacental insufficiency (UPI) has been reported to be associated with lower or greater risk of infant retinopathy of prematurity (ROP). UPI induces erythropoietin (EPO) expression, and EPO, as a ligand, can be vasoprotective against high oxygen in experimental models but was not found to be neuroprotective for premature infants in a recent clinical trial. To dissect the role of ligand and receptor signaling, we tested the hypothesis that signaling through the EPO receptor (EPOR) in the setting of maternal UPI reduced high oxygen-induced retinal vascular loss. We used humanized EPOR knock-in mice (hWT) with hypoactive signaling through the EPOR and littermate control wild-type mice (mWT) in a combined UPI/oxygen-induced retinopathy (OIR) mouse model.

Methods : Heterozygous hWT mice were bred for homozygous hWT and littermate homozygous mWT pups. On embryonic day 12.5, pregnant hWT dams were implanted with microosmotic pumps that released a thromboxane A2 analogue dissolved in 0.5% ethanol to create UPI or 0.5% ethanol (control). After birth, pups were transferred to a foster heterozygous hWT dam. Postnatal day 7 (p7) pups with foster dams were placed into the mouse OIR model (75% O2) for 5 days. At p12, pups were euthanized, and blood, serum, and retinae were collected. Retinal flat mounts were stained with isolectin, and imaged with a fluorescent microscope. The images were analyzed for avascular to total retinal area (AVA) with ImageJ. Serum EPO was measured by ELISA. Hematocrits were read with a capillary microhematocrit reader. Data were analyzed with 1) a multilevel linear regression model with eyes nested within animals and animals nested within litters for AVA, and 2) a two tailed t-test for serum EPO and hematocrit.

Results : Compared to mWT, hWT mice born to dams with UPI or control dams had reduced hematocrit (p<0.0001) despite increased serum EPO (p<0.0001). In p12 mWT pups born to dams with UPI (mWt;UPI), there was reduced AVA (p<0.05) compared to mWT;control. However, in p12 hWT;UPI, there was no difference in AVA (p=0.766) compared to hWT;control.

Conclusions : Maternal UPI-induced endogenous EPOR signaling may provide some retinal vascular protection from hyperoxia-mediated vascular loss. Further studies are needed to determine the mechanisms involved in EPO/EPOR or other receptor mediated vascular protection.

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

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