June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Glial cells regulate pericyte-driven capillary deficits in glaucoma
Author Affiliations & Notes
  • Deborah Villafranca-Baughman
    Department of Neuroscience, Universite de Montreal Faculte de Medecine, Montreal, Quebec, Canada
    Department of Neuroscience, Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada
  • Luis Alarcon-Martinez
    Centre for Eye Research Australia Ltd, East Melbourne, Victoria, Australia
    Department of Neuroscience, Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada
  • Nicolas Belforte
    Department of Neuroscience, Universite de Montreal Faculte de Medecine, Montreal, Quebec, Canada
    Department of Neuroscience, Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada
  • Heberto Quintero
    Department of Neuroscience, Universite de Montreal Faculte de Medecine, Montreal, Quebec, Canada
    Department of Neuroscience, Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada
  • Florence Dotigny
    Department of Neuroscience, Universite de Montreal Faculte de Medecine, Montreal, Quebec, Canada
    Department of Neuroscience, Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada
  • Adriana Di Polo
    Department of Neuroscience, Universite de Montreal Faculte de Medecine, Montreal, Quebec, Canada
    Department of Neuroscience, Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada
  • Footnotes
    Commercial Relationships   Deborah Villafranca-Baughman None; Luis Alarcon-Martinez None; Nicolas Belforte None; Heberto Quintero None; Florence Dotigny None; Adriana Di Polo None
  • Footnotes
    Support  A. Di polo from The Glaucoma Foundation (TGF, NYC) and the Canadian Institutes of Health Research (CIHR). D. Villafranca-Baughman is supported by a graduate scholarship from the Fonds de recherche Santé – Québec (FRQS), and A. Di Polo holds a Canada Research Chair (Tier 1)
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 3259. doi:
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    • Get Citation

      Deborah Villafranca-Baughman, Luis Alarcon-Martinez, Nicolas Belforte, Heberto Quintero, Florence Dotigny, Adriana Di Polo; Glial cells regulate pericyte-driven capillary deficits in glaucoma. Invest. Ophthalmol. Vis. Sci. 2023;64(8):3259.

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

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Abstract

Purpose : Neurovascular coupling (NVC) is a physiological mechanism that matches blood flow with neuronal activity to bring oxygen and nutrients to active neurons. We recently demonstrated that pericytes regulate NVC in the retina and that pericyte dysfunction leads to reduced blood flow during ocular hypertension (OHT). Here, we asked whether glial cells in the retina and optic nerve contribute to pericyte responses by probing the mechanisms underlying capillary deficits.

Methods : OHT was induced by intracameral injection of magnetic microbeads in reporter mice to visualize pericytes and/or glial cells as well as calcium (Ca2+) transients (GCaMP6f). Two-photon laser scanning microscopy (TPLSM) was combined with a femtomolar delivery system for longitudinal trans-scleral imaging of glial-pericyte-capillary responses in living mice. A set of complementary techniques was used to probe cell-specific molecular changes including sc-RNAseq, qRT-PCR, and immunohistochemistry (IHC).

Results : We found a substantial reduction of capillary blood flow at pericyte locations concomitant with intrapericyte Ca2+ increase in eyes subjected to OHT relative to sham controls (N=9 mice/group, n= 200-376 capillaries, Student’s t-test, p<0.001). Single cell (sc)-RNAseq revealed changes in Ca2+ homeostasis pathways including upregulation of transcripts encoding the Ca2+ binding protein S100B in glial cells. IHC confirmed S100B upregulation in Müller cells and astrocytes in the retina and optic nerve head. Delivery of recombinant S100B protein exacerbated intrapericyte Ca2+ influx and blood flow impairment (N=11 mice/group, n= 62-76 capillaries, Student’s t-test, p<0.001). In contrast, administration of S100B function blocking antibodies (FBA) decreased Ca2+ in pericytes and improved capillary blood flow during OHT stress (blood flow - sham: 100%, n=128 capillaries OHT + control antibody: 65 ± 19%, n=153 capillaries; OHT + FBA: 97 ± 5%, n=576 capillaries, N=4-9 mice/group, ANOVA, p<0.001). Remarkably, S100B neutralization protected RGCs from OHT-induced death (% survival – sham: 100%, OHT + FBA: 93%, OHT + control: 65%, N=11-13 mice/group, ANOVA, p<0.001).

Conclusions : Our data reveal a novel role of glial cells in the regulation of pericyte responses to OHT stress and identify S100B as a critical glia-derived player in NVC deficits.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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