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

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 fl...

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Autores principales: Holden, Joseph M., Al Hussein Al Awamlh, Sara, Croteau, Louis-Philippe, Boal, Andrew M., Rex, Tonia S., Risner, Michael L., Calkins, David J., Wareham, Lauren K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8954518/
https://www.ncbi.nlm.nih.gov/pubmed/35328488
http://dx.doi.org/10.3390/ijms23063066
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author Holden, Joseph M.
Al Hussein Al Awamlh, Sara
Croteau, Louis-Philippe
Boal, Andrew M.
Rex, Tonia S.
Risner, Michael L.
Calkins, David J.
Wareham, Lauren K.
author_facet Holden, Joseph M.
Al Hussein Al Awamlh, Sara
Croteau, Louis-Philippe
Boal, Andrew M.
Rex, Tonia S.
Risner, Michael L.
Calkins, David J.
Wareham, Lauren K.
author_sort Holden, Joseph M.
collection PubMed
description 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.
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spelling pubmed-89545182022-03-26 Dysfunctional cGMP Signaling Leads to Age-Related Retinal Vascular Alterations and Astrocyte Remodeling in Mice Holden, Joseph M. Al Hussein Al Awamlh, Sara Croteau, Louis-Philippe Boal, Andrew M. Rex, Tonia S. Risner, Michael L. Calkins, David J. Wareham, Lauren K. Int J Mol Sci Article 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. MDPI 2022-03-12 /pmc/articles/PMC8954518/ /pubmed/35328488 http://dx.doi.org/10.3390/ijms23063066 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Holden, Joseph M.
Al Hussein Al Awamlh, Sara
Croteau, Louis-Philippe
Boal, Andrew M.
Rex, Tonia S.
Risner, Michael L.
Calkins, David J.
Wareham, Lauren K.
Dysfunctional cGMP Signaling Leads to Age-Related Retinal Vascular Alterations and Astrocyte Remodeling in Mice
title Dysfunctional cGMP Signaling Leads to Age-Related Retinal Vascular Alterations and Astrocyte Remodeling in Mice
title_full Dysfunctional cGMP Signaling Leads to Age-Related Retinal Vascular Alterations and Astrocyte Remodeling in Mice
title_fullStr Dysfunctional cGMP Signaling Leads to Age-Related Retinal Vascular Alterations and Astrocyte Remodeling in Mice
title_full_unstemmed Dysfunctional cGMP Signaling Leads to Age-Related Retinal Vascular Alterations and Astrocyte Remodeling in Mice
title_short Dysfunctional cGMP Signaling Leads to Age-Related Retinal Vascular Alterations and Astrocyte Remodeling in Mice
title_sort dysfunctional cgmp signaling leads to age-related retinal vascular alterations and astrocyte remodeling in mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8954518/
https://www.ncbi.nlm.nih.gov/pubmed/35328488
http://dx.doi.org/10.3390/ijms23063066
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