Dysfunctional cGMP Signaling Leads to Age-Related Retinal Vascular Alterations and Astrocyte Remodeling in Mice.

Joseph M Holden,Andrew M Boal,Lauren K Wareham,Sara Al Hussein Al Awamlh,Tonia S Rex,David J Calkins,Louis-Philippe Croteau,Michael L Risner

doi:10.3390/ijms23063066

Joseph M Holden, Andrew M Boal + Show 6 more

Open Access

https://doi.org/10.3390/ijms23063066

Copy DOI

Abstract

The nitric oxide–guanylyl cyclase-1–cyclic guanylate monophosphate (NO–GC-1–cGMP) pathway is integral to the control of vascular tone and morphology. Mice lacking the alpha catalytic domain of guanylate cyclase (GC1−/−) develop retinal ganglion cell (RGC) degeneration with age, with only modest fluctuations in intraocular pressure (IOP). Increasing the bioavailability of cGMP in GC1−/− mice prevents neurodegeneration independently of IOP, suggesting alternative mechanisms of retinal neurodegeneration. In continuation to these studies, we explored the hypothesis that dysfunctional cGMP signaling leads to changes in the neurovascular unit that may contribute to RGC degeneration. We assessed retinal vasculature and astrocyte morphology in young and aged GC1−/− and wild type mice. GC1−/− mice exhibit increased peripheral retinal vessel dilation and shorter retinal vessel branching with increasing age compared to Wt mice. Astrocyte cell morphology is aberrant, and glial fibrillary acidic protein (GFAP) density is increased in young and aged GC1−/− mice, with areas of dense astrocyte matting around blood vessels. Our results suggest that proper cGMP signaling is essential to retinal vessel morphology with increasing age. Vascular changed are preceded by alterations in astrocyte morphology which may together contribute to retinal neurodegeneration and loss of visual acuity observed in GC1−/− mice.

Highlights

The nitric oxide–guanylyl cyclase-1–cyclic guanylate monophosphate (NO–GC1–cGMP) signaling pathway is integral to the control of vascular tone and morphology [1].Recently, studies in humans and mice have implicated the NO–cGMP pathway in glaucomarelated retinal neurodegeneration
Regions of interest (ROIs) from mid and peripheral retinas were selected so that almost the entire retina was analyzed without overlap; an outline of the process is shown in Supplemental Figure S1A
Previous work has implicated dysfunctional NO–cGMP signaling in the pathophysiol3

Summary

Introduction

CGMP) signaling pathway is integral to the control of vascular tone and morphology [1]. Studies in humans and mice have implicated the NO–cGMP pathway in glaucomarelated retinal neurodegeneration. Multiple genetic epidemiology studies have implicated aberrant NO–cGMP signaling in glaucoma disease pathology [2–5]. Physiological studies have detected lower levels of NO and cGMP in the serum and aqueous humor of glaucoma patients [6,7]. Neurodegeneration of retina ganglion cells (RGCs) in glaucoma is due to an increase in sensitivity to intraocular pressure (IOP). Despite IOP-lowering regimens, patients still progress to vision loss and, identification of other mechanisms by which RGCs may develop increased sensitivity to IOP is warranted. Our previous work identified cGMP signaling as an IOP-independent neuroprotective target for RGC neurodegeneration [8]

Methods

Results

Conclusion