June 2021
Volume 62, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2021
Pericyte dysfunction promotes neurovascular deficits in glaucoma
Author Affiliations & Notes
  • Luis Alarcon-Martinez
    Neuroscience, Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada
  • Yukihiro Shiga
    Neuroscience, Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada
  • Nicolas Belforte
    Neuroscience, Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada
  • Deborah Villafranca-Baughman
    Neuroscience, Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada
  • Jorge Cueva Vargas
    Neuroscience, Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada
  • Heberto Quintero
    Neuroscience, Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada
  • Florence Dotigny
    Neuroscience, Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada
  • Adriana Di Polo
    Neuroscience, Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada
  • Footnotes
    Commercial Relationships   Luis Alarcon-Martinez, None; Yukihiro Shiga, None; Nicolas Belforte, None; Deborah Villafranca-Baughman, None; Jorge Cueva Vargas, None; Heberto Quintero, None; Florence Dotigny, None; Adriana Di Polo, None
  • Footnotes
    Support  Canadian Institutes of Health Research Grant PJT-152934
Investigative Ophthalmology & Visual Science June 2021, Vol.62, 1864. doi:
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      Luis Alarcon-Martinez, Yukihiro Shiga, Nicolas Belforte, Deborah Villafranca-Baughman, Jorge Cueva Vargas, Heberto Quintero, Florence Dotigny, Adriana Di Polo; Pericyte dysfunction promotes neurovascular deficits in glaucoma. Invest. Ophthalmol. Vis. Sci. 2021;62(8):1864.

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

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Abstract

Purpose : Major vascular defects are observed in glaucoma patients, but the mechanisms underlying these alterations are poorly understood. Pericytes, the contractile cells that wrap along capillaries, regulate blood flow in response to metabolic demand. We recently identified inter-pericyte tunneling nanotubes (IP-TNTs), fine tubular processes that connect two distally-located pericytes and are essential for neurovascular coupling. Here, we asked whether pericytes/IP-TNTs contribute to neurovascular dysfunction in glaucoma.

Methods : Ocular hypertension (OHT) was induced by injecting magnetic microbeads into the anterior chamber of mice. Two-photon laser scanning microscopy was used for live imaging of retinal pericytes, IP-TNTs, calcium (Ca2+) signals, light-evoked capillary dynamics and blood flow changes. Ca2+influx induces pericyte contraction, thus we generated micecarrying a pericyte-specific Ca2+indicator (NG2-GCaMP6), and mice with a pericyte-specific conditional deletion of the voltage-dependent Ca2+channel alpha 1C subunit (Cav1.2) (CACNA1Cnull) for analysis of microvascular responses.

Results : Our data show early and sustained reduction of capillary diameter and blood flow at pericyte locations in eyes subjected to OHT relative to sham-operated controls (blood flow - sham: 15 ± 0.6 red blood cell (RBC)/s, OHT-2 weeks: 11.6 ± 0.8 RBC/s, n=58-86 capillaries, N=5-6 mice/group, Student’s t-test p<0.01). Vascular deficits correlated with a substantial increase in the number of pericytes with elevated Ca2+, visualized in NG2-GCaMP6 mice (sham: 11.9 ± 2.1 pericytes, OHT-2 weeks: 41.6 ± 2.4 pericytes, n=167-235 pericytes, N=5-13 mice/group, Student’s t-test p<0.001). OHT led to IP-TNT rupture with consequent deficits in light-evoked neurovascular coupling (blood flow change - sham: 16.2 ± 3.6 %, OHT-2 weeks: 4.7 ± 1.0 %, n=29-32 capillaries, N=5-6 mice/group, Student’s t-test p<0.01). Remarkably, selective blockage of Ca2+influx to pericytes (CACNA1Cnull mice) restored capillary dynamics, blood flow, and light-evoked neurovascular coupling in glaucomatous retinas.

Conclusions : Early calcium-induced pericyte contraction in glaucoma leads to reduced capillary diameter/blood flow and IP-TNT rupture leading to neurovascular impairment. Our data reveal a critical role for pericytes in OHT-related vascular deficits, and suggest that restoration of Ca2+homeostasis in pericytes is effective to rescue neurovascular function in glaucoma.

This is a 2021 ARVO Annual Meeting abstract.

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