Pericyte dysfunction and loss of interpericyte tunneling nanotubes promote neurovascular deficits in glaucoma

Author(s): Luis Alarcon-Martinez (1,2), Yukihiro Shiga (3,2), Deborah Villafranca-Baughman )3,2), Nicolas Belforte (3,2), Heberto Quintero (3,2), Florence Dotigny (3,2), Jorge L Cueva Vargas (3,2), Adriana Di Polo (1,2)

1 Department of Neuroscience, Université de Montréal, Montréal, QC H3C 3J7, Canada; luis.alarconmartinez@unimelb.edu.au. adriana.di.polo@umontreal.ca.
2 Neuroscience Division, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, QC H2X 0A9, Canada.
3 Department of Neuroscience, Université de Montréal, Montréal, QC H3C 3J7, Canada.

Reduced blood flow and impaired neurovascular coupling are recognized features of glaucoma, the leading cause of irreversible blindness worldwide, but the mechanisms underlying these defects are unknown. Retinal pericytes regulate microcirculatory blood flow and coordinate neurovascular coupling through interpericyte tunneling nanotubes (IP-TNTs). Using two-photon microscope live imaging of the mouse retina, we found reduced capillary diameter and impaired blood flow at pericyte locations in eyes with high intraocular pressure, the most important risk factor to develop glaucoma.

We show that IP-TNTs are structurally and functionally damaged by ocular hypertension, a response that disrupted light-evoked neurovascular coupling. Pericyte-specific inhibition of excessive Ca2+ influx rescued hemodynamic responses, protected IP-TNTs and neurovascular coupling, and enhanced retinal neuronal function as well as survival in glaucomatous retinas. Our study identifies pericytes and IP-TNTs as potential therapeutic targets to counter ocular pressure-related microvascular deficits, and provides preclinical proof of concept that strategies aimed to restore intrapericyte calcium homeostasis rescue autoregulatory blood flow and prevent neuronal dysfunction.

Copyright © 2022 the Author(s). Published by PNAS.

Proc Natl Acad Sci U S A. 2022 Feb 15;119(7):e2110329119. doi: 10.1073/pnas.2110329119.

PMID: 35135877 PMCID: PMC8851476 DOI: 10.1073/pnas.2110329119

Keywords: calcium homeostasis; glaucoma; neurovascular coupling; pericytes; retina

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