Pericyte dysfunction and loss of interpericyte tunneling nanotubes promote neurovascular deficits in glaucoma
Reduced blood flow and impaired neurovascular coupling are recognized features of glaucoma, the leading cause of irreversible blindness worldwide, but the mechanisms underlying these abnormalities remain unknown. Retinal pericytes regulate microcirculatory blood flow and coordinate neurovascular coupling through interpericyte tunneling nanotubes (IP-TNTs). Using live two-photon microscopy imaging of the mouse retina, we observed reduced capillary diameter and impaired blood flow at the pericytes in eyes with elevated intraocular pressure, the main risk factor for the development of glaucoma. We show that IP-TNTs are structurally and functionally damaged by ocular hypertension, a response that disrupts light-triggered neurovascular coupling. Pericyte-specific inhibition of excessive Ca2+ influx restored hemodynamic responses, protected IP-TNTs and neurovascular coupling, and improved retinal neuronal function and survival in glaucomatous retinas. Our study identifies pericytes and IP-TNTs as potential therapeutic targets to counteract ocular pressure-related microvascular deficits, and provides preclinical proof of concept that strategies aimed at restoring intrapericytic calcium homeostasis can rescue autoregulated blood flow and prevent neuronal dysfunction.
