June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Regulation of neurovascular coupling in proliferative retinopathy through a functional interaction between RORα and semaphorin 3E
Author Affiliations & Notes
  • Chi-Hsiu Liu
    Ophthalmology, Boston Children's Hospital, Boston, Massachusetts, United States
  • Ye Sun
    Ophthalmology, Boston Children's Hospital, Boston, Massachusetts, United States
  • Zhongxiao Wang
    Ophthalmology, Boston Children's Hospital, Boston, Massachusetts, United States
  • Steven Meng
    Ophthalmology, Boston Children's Hospital, Boston, Massachusetts, United States
  • Samuel Burnim
    Ophthalmology, Boston Children's Hospital, Boston, Massachusetts, United States
  • Jing Chen
    Ophthalmology, Boston Children's Hospital, Boston, Massachusetts, United States
  • Footnotes
    Commercial Relationships   Chi-Hsiu Liu, None; Ye Sun, None; Zhongxiao Wang, None; Steven Meng, None; Samuel Burnim, None; Jing Chen, None
  • Footnotes
    Support  This work was supported by NIH/NEI (R01 EY024963), Boston Children's Hospital (BCH) Career Development Award, BrightFocus Foundation and BCH Ophthalmology Foundation.
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 3651. doi:
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      Chi-Hsiu Liu, Ye Sun, Zhongxiao Wang, Steven Meng, Samuel Burnim, Jing Chen; Regulation of neurovascular coupling in proliferative retinopathy through a functional interaction between RORα and semaphorin 3E. Invest. Ophthalmol. Vis. Sci. 2017;58(8):3651.

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

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Abstract

Purpose : Dysregulated crosstalk between the retinal neurons and vasculature contributes to the pathogenesis of proliferative retinopathy, a leading cause of blindness. Class 3 semaphorins (Sema3s) are neuron-secreted axonal and vascular guidance factors protective for suppressing disoriented vascular growth in retinopathy but the upstream regulators in retinas neurons remain unclear. Here we investigated the role of retinoic acid receptor-related orphan receptor alpha (RORα), a lipid-sensing nuclear receptor and transcription factor, in the regulation of Sema3-mediated neurovascular coupling in proliferative retinopathy.

Methods : A mouse model of oxygen-induced retinopathy (OIR) mimicking proliferative retinopathy was used. RORα and Sema3s expressing levels were analyzed in OIR retinas compared with normoxic controls. Potential genes containing RORα-binding DNA elements (ROREs) were analyzed by chromatin immunoprecipitation assay, followed by verification with qPCR. RORα and Sema3E were localized with immunohistochemistry. Sema3E promoter-driven luciferase reporter assay was performed using HEK293T cells treated with RORα-expressing vectors or a synthetic RORα inverse agonist (SR1001). Pathologic retinal neovascularization (NV) in OIR was quantified in RORα-deficient staggerer (Sg/Sg) and wild type (WT) mice, with intravitreal injection of Sema3E or control shRNA expressed from adeno-associated viral vectors.

Results : Deficiency of RORα substantially induced expression of Sema3E (~2-fold uincrease) and decreased NV in Sg/Sg OIR retinas compared with littermate WT controls. Both RORα and Sema3E were localized in retinal ganglion cells. RORα directly recognized and bound to a specific RORE on the promoter of Sema3E in the retinas, showing approximately 2-fold enrichment compared with the positive control. RORα significantly suppressed Sema3E promoter-driven transcriptional activity (>50%) in a dose-dependent manner; conversely, SR1001 enhanced Sema3E promoter-driven luciferase activity. Moreover, suppression of Sema3e in Sg/Sg retinas promoted disoriented pathologic NV in OIR and partially abolished the protective vascular effects of RORα-deficiency.

Conclusions : Our findings suggest that RORα is a novel transcriptional regulator of Sema3E-mediated neurovascular coupling in retinopathy. RORα-Sema3E axis may serve as a potential pathway for treating neovascular eye diseases.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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