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

被引:46
作者
Alarcon-Martinez, Luis [1 ,2 ,3 ]
Shiga, Yukihiro [1 ,2 ]
Villafranca-Baughman, Deborah [1 ,2 ]
Belforte, Nicolas [1 ,2 ]
Quintero, Heberto [1 ,2 ]
Dotigny, Florence [1 ,2 ]
Vargas, Jorge L. Cueva [1 ,2 ]
Di Polo, Adriana [1 ,2 ]
机构
[1] Univ Montreal, Dept Neurosci, Montreal, PQ H3C 3J7, Canada
[2] Univ Montreal, Neurosci Div, Ctr Rech, Ctr Hosp, Montreal, PQ H2X 0A9, Canada
[3] Univ Melbourne, Ctr Eye Res Australia, Melbourne, Vic 3002, Australia
基金
加拿大健康研究院;
关键词
neurovascular coupling; pericytes; retina; glaucoma; calcium homeostasis; OCULAR BLOOD-FLOW; FLICKER LIGHT; CELL-TYPES; INHIBITION; HYPERTENSION; ASSOCIATION; DYNAMICS; HEALTH;
D O I
10.1073/pnas.2110329119
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
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页数:11
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