June 2021
Volume 62, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2021
Identification of ESR1 in aqueous humor outflow pathway tissues
Author Affiliations & Notes
  • Hannah Youngblood
    Augusta University Department of Cellular Biology and Anatomy, Augusta, Georgia, United States
  • Jingwen Cai
    Augusta University Department of Cellular Biology and Anatomy, Augusta, Georgia, United States
  • Kristin Perkumas
    Department of Ophthalmology, Duke University, Durham, North Carolina, United States
  • Hongfang Yu
    Augusta University Department of Cellular Biology and Anatomy, Augusta, Georgia, United States
  • Michael A Hauser
    Department of Medicine, Duke University, Durham, North Carolina, United States
  • W. Daniel Stamer
    Department of Ophthalmology, Duke University, Durham, North Carolina, United States
  • Yutao Liu
    Augusta University Department of Cellular Biology and Anatomy, Augusta, Georgia, United States
    Augusta University Center for Biotechnology and Genomic Medicine, Augusta, Georgia, United States
  • Footnotes
    Commercial Relationships   Hannah Youngblood, None; Jingwen Cai, None; Kristin Perkumas, None; Hongfang Yu, None; Michael Hauser, None; W. Daniel Stamer, None; Yutao Liu, None
  • Footnotes
    Support  We thank the financial support from The Glaucoma Foundation, The Glaucoma Research Foundation, The BrightFocus Foundation, NIH R01EY023242, R21EY028671, R01EY022359, R01EY023287, F31EY031973, and P30EY031631. Financial support from Fight for Sight is gratefully acknowledged.
Investigative Ophthalmology & Visual Science June 2021, Vol.62, 1497. doi:
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      Hannah Youngblood, Jingwen Cai, Kristin Perkumas, Hongfang Yu, Michael A Hauser, W. Daniel Stamer, Yutao Liu; Identification of ESR1 in aqueous humor outflow pathway tissues. Invest. Ophthalmol. Vis. Sci. 2021;62(8):1497.

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

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Abstract

Purpose : Elevated intraocular pressure (IOP) is the only treatable risk factor for primary open-angle glaucoma (POAG). Our previous pathway analysis of IOP-associated loci identified 2 networks focused on an unspecified estrogen receptor and estrogen receptor 1 (ESR1), respectively (Liu 2020). Here we seek to confirm the role of ESR1 signaling in the aqueous humor (AH) outflow pathway.

Methods : We examined which 17 IOP-associated genes in the estrogen receptor networks were specifically expressed in a single-cell RNA sequencing (scRNA-Seq) dataset of human outflow tissue (van Zyl 2020) as well as an RNA-Seq dataset of nonglaucomatous human TM (n=4) and Schlemms Canal (SC) (n=2) cells. To confirm ESR1 activity in the outflow pathway, we examined its protein expression in nonglaucomatous human (n=4) and mouse outflow tissues (n=2) by antibody-based immunofluorescence, using tissue from an Esr1-/- mouse as a negative control (n=1). We also measured 17β-estradiol (E2) concentration in glaucomatous (n=4) and nonglaucomatous (n=4) human AH using an ELISA kit (Enzo Life Sciences).

Results : Seven IOP genes from the estrogen receptor networks (i.e., CAV2, FBXO32, SIX3, FOXC1, SPTBN1, TCF7L2, and TNXB) were expressed in ≥1 cell clusters defined by scRNA-Seq, including cell clusters localized to the TM, SC, collector channels, ciliary muscle, Schwalbe’s line, vascular endothelium, etc. As confirmation, in a separate RNA-Seq study of human TM and SC cells, 8 genes of interest (i.e., CAV2, ETS1, FBXO32, VEGFC, FOXC1, SPTBN1, TCF7L2, and TMEM119) were highly expressed (i.e., FPKM ≥ 10) in either TM or SC cells, with SPTBN1 having the highest expression (i.e., 85.85 FPKM and 85.83 FPKM). Esr1 protein was expressed in the iridocorneal angle of female B6J wild-type, but not Esr1-/- mice. Similarly, ESR1 protein was expressed in human TM/SC. E2 was present in both glaucomatous (34.46 ± 7.08 pg/mL) and nonglaucomatous human (37.90 ± 14.80 pg/mL) AH (p>0.05).

Conclusions : Many IOP-associated genes within the estrogen receptor networks are highly expressed in the outflow pathway including in the TM, SC, ciliary muscle, and vascular endothelium. The confirmation of ESR1 protein expression in human and mouse outflow tissues and the presence of E2 in AH further supports a possible function of ESR1 signaling in IOP regulation through modulation of AH outflow.

This is a 2021 ARVO Annual Meeting abstract.

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