{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T23:44:55Z","timestamp":1782949495474,"version":"3.54.5"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T00:00:00Z","timestamp":1782950400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Neurosci."],"abstract":"<jats:p>Astrocytes regulate metabolic exchange between the vasculature and neurons in the central nervous system (CNS). In the retina of the eye, also a component of the CNS, astrocyte endfeet couple to vascular elements to mediate glucose uptake via the glucose transporter GLUT1 and shuttle metabolic resources to the axons of retinal ganglion cells (RGCs), which provide visual input to the brain. In addition to its own transcriptional regulation, GLUT1 is also modulated by signaling pathways that influence its subcellular localization at the astrocyte-vascular interface. For example, cyclic guanosine monophosphate (cGMP) signaling, a key regulator of vascular tone, is associated with changes in retinal astrocyte morphology and is implicated in age-related loss of RGCs, suggesting a potential role in astrocyte function within the neurovascular unit. Here, we tested this possibility directly by investigating the effects of 8-Br-cGMP on astrocyte morphology, vascular interactions, and GLUT1 localization in the retina. Using a transgenic mouse that allows resolution of individual astrocytes in great detail across the retina (the G-MORF mouse), we show that acute elevation of 8-Br-cGMP increases astrocyte coverage area without altering overall vascular structure. 8-Br-cGMP treatment was also associated with enhanced astrocyte-vascular association, reflected by increased endfoot coverage of blood vessels and altered scaling of astrocyte contact with vessel size. Treatment to increase cGMP signaling promoted redistribution of GLUT1 to astrocyte perivascular endfeet without changing overall levels of GLUT1. Together, these findings indicate that increased cGMP signaling induces coordinated structural and molecular remodeling of astrocytes at the vascular interface. These results provide important insight into how cyclic nucleotide signaling pathways may regulate astrocyte organization in the retina and suggests a potential role for cGMP in modulating astrocyte-vascular interactions within the neurovascular unit.<\/jats:p>","DOI":"10.3389\/fncel.2026.1870679","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T23:10:14Z","timestamp":1782947414000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Pharmacological activation of cGMP signaling promotes astrocyte remodeling and enrichment of perivascular GLUT1 in the murine retina"],"prefix":"10.3389","volume":"20","author":[{"given":"Kristin L.","family":"Clark","sequence":"first","affiliation":[{"name":"Vanderbilt Eye Institute, Vanderbilt University Medical Center","place":["Nashville, TN, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shane","family":"Mecca","sequence":"additional","affiliation":[{"name":"Vanderbilt Eye Institute, Vanderbilt University Medical Center","place":["Nashville, TN, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elio","family":"Almaoui","sequence":"additional","affiliation":[{"name":"Vanderbilt Eye Institute, Vanderbilt University Medical Center","place":["Nashville, TN, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia L.","family":"Bossardet","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Miami","place":["Miami, FL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph M.","family":"Holden","sequence":"additional","affiliation":[{"name":"Vanderbilt Eye Institute, Vanderbilt University Medical Center","place":["Nashville, TN, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Calkins","sequence":"additional","affiliation":[{"name":"Vanderbilt Eye Institute, Vanderbilt University Medical Center","place":["Nashville, TN, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren K.","family":"Wareham","sequence":"additional","affiliation":[{"name":"Vanderbilt Eye Institute, Vanderbilt University Medical Center","place":["Nashville, TN, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,2]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1038\/nrn1824","article-title":"Astrocyte-endothelial interactions at the blood-brain barrier","volume":"7","author":"Abbott","year":"2006","journal-title":"Nat. Rev. Neurosci."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/j.bbr.2012.11.025","article-title":"Plastic changes in the astrocyte GLUT1 glucose transporter and beta-tubulin microtubule protein following voluntary exercise in mice","volume":"240","author":"Allen","year":"2013","journal-title":"Behav. Brain Res."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1038\/nature09613","article-title":"Glial and neuronal control of brain blood flow","volume":"468","author":"Attwell","year":"2010","journal-title":"Nature"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"488","DOI":"10.1124\/pr.58.3.5","article-title":"Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use","volume":"58","author":"Bender","year":"2006","journal-title":"Pharmacol. Rev."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"1391","DOI":"10.1016\/s0024-3205(01)01222-x","article-title":"Inhibition of glucose transport by cyclic GMP in cardiomyocytes","volume":"69","author":"Bergemann","year":"2001","journal-title":"Life Sci."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"14937","DOI":"10.1073\/pnas.0405315101","article-title":"Astrocytes generate Na+\u2212mediated metabolic waves","volume":"101","author":"Bernardinelli","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1111\/j.1471-4159.2007.04464.x","article-title":"The cyclic GMP-protein kinase G pathway regulates cytoskeleton dynamics and motility in astrocytes","volume":"102","author":"Boran","year":"2007","journal-title":"J. Neurochem."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1007\/s11064-025-04512-w","article-title":"Sex-specific properties of astrocytes: from development to evolutionary insights","volume":"50","author":"Bortolanza","year":"2025","journal-title":"Neurochem. Res."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"4167","DOI":"10.1038\/s41598-025-34243-5","article-title":"Soluble guanylate cyclase deficiency drives retinal ganglion cell neurodegeneration with age in female mice through disrupted oxidative metabolism","volume":"16","author":"Bossardet","year":"2026","journal-title":"Sci. Rep."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1016\/j.neuroscience.2004.09.011","article-title":"Glucose transporter plasticity during memory processing","volume":"130","author":"Choeiri","year":"2005","journal-title":"Neuroscience"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1146\/annurev-biochem-050410-100030","article-title":"Structure and regulation of soluble guanylate cyclase","volume":"81","author":"Derbyshire","year":"2012","journal-title":"Annu. Rev. Biochem."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"e79977","DOI":"10.1371\/journal.pone.0079977","article-title":"Early decline in glucose transport and metabolism precedes shift to ketogenic system in female aging and Alzheimer\u2019s mouse brain: implication for bioenergetic intervention","volume":"8","author":"Ding","year":"2013","journal-title":"PLoS One"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"eadc9020","DOI":"10.1126\/science.adc9020","article-title":"Molecular basis of astrocyte diversity and morphology across the CNS in health and disease","volume":"378","author":"Endo","year":"2022","journal-title":"Science"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1124\/pr.110.002907","article-title":"cGMP-dependent protein kinases and cGMP phosphodiesterases in nitric oxide and cGMP action","volume":"62","author":"Francis","year":"2010","journal-title":"Pharmacol. Rev."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1007\/s00210-019-01779-z","article-title":"cGMP: a unique 2nd messenger molecule \u2013 recent developments in cGMP research and development","volume":"393","author":"Friebe","year":"2020","journal-title":"Naunyn Schmiedeberg\u2019s Arch. Pharmacol."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1113\/expphysiol.2010.053132","article-title":"Bidirectional control of arteriole diameter by astrocytes","volume":"96","author":"Gordon","year":"2011","journal-title":"Exp. Physiol."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"1724","DOI":"10.3390\/cells13201724","article-title":"Sex differences in astrocyte activity","volume":"13","author":"Gozlan","year":"2024","journal-title":"Cells"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"4033","DOI":"10.1002\/j.1460-2075.1991.tb04979.x","article-title":"A CAAX or a CAAL motif and a second signal are sufficient for plasma membrane targeting of RAS proteins","volume":"10","author":"Hancock","year":"1991","journal-title":"EMBO J."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"9750","DOI":"10.1038\/s41467-025-65487-4","article-title":"Molecular profiling of brain endothelial cell to astrocyte endfoot communication in mouse and human","volume":"16","author":"Hill","year":"2025","journal-title":"Nat. Commun."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"3066","DOI":"10.3390\/ijms23063066","article-title":"Dysfunctional cGMP signaling leads to age-related retinal vascular alterations and astrocyte remodeling in mice","volume":"23","author":"Holden","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"1244679","DOI":"10.3389\/fnins.2023.1244679","article-title":"Retinal astrocyte morphology predicts integration of vascular and neuronal architecture","volume":"17","author":"Holden","year":"2023","journal-title":"Front. Neurosci."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"3275","DOI":"10.1523\/jneurosci.2010-20.2021","article-title":"Reduction of Glut1 in the neural retina but not the RPE alleviates polyol accumulation and normalizes early characteristics of diabetic retinopathy","volume":"41","author":"Holoman","year":"2021","journal-title":"J. Neurosci."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.neuron.2017.07.030","article-title":"The neurovascular unit coming of age: a journey through neurovascular coupling in health and disease","volume":"96","author":"Iadecola","year":"2017","journal-title":"Neuron"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/(sici)1098-1136(199805)23:1<>3.0.co;2-b","article-title":"Structural organization of the perivascular astrocyte endfeet and their relationship with the endothelial glucose transporter: a confocal microscopy study","volume":"23","author":"Kacem","year":"1998","journal-title":"Glia"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"1657","DOI":"10.1096\/fj.05-4107com","article-title":"Vitamin C enters mitochondria via facilitative glucose transporter 1 (Glut1) and confers mitochondrial protection against oxidative injury","volume":"19","author":"Kc","year":"2005","journal-title":"FASEB J."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1002\/(sici)1520-7560(199907\/08)15:4<>3.0.co;2-z","article-title":"Glucose transport in brain and retina: implications in the management and complications of diabetes","volume":"15","author":"Kumagai","year":"1999","journal-title":"Diabetes Metab. Res. Rev."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"20","DOI":"10.3390\/jcdd5020020","article-title":"cGMP signaling and vascular smooth muscle cell plasticity","volume":"5","author":"Lehners","year":"2018","journal-title":"J. Cardiovasc. Dev. Dis."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"a020388","DOI":"10.1101\/cshperspect.a020388","article-title":"Astrocyte regulation of blood flow in the brain","volume":"7","author":"MacVicar","year":"2015","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1002\/jnr.490420404","article-title":"Immunolocalization of GLUT1 and GLUT3 glucose transporters in primary cultured neurons and glia","volume":"42","author":"Maher","year":"1995","journal-title":"J. Neurosci. Res."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"1094","DOI":"10.1002\/glia.20990","article-title":"The perivascular astroglial sheath provides a complete covering of the brain microvessels: an electron microscopic 3D reconstruction","volume":"58","author":"Mathiisen","year":"2010","journal-title":"Glia"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1016\/0006-8993(94)90893-1","article-title":"Immunocytochemical distribution of the brain glucose transporter (GLUT 1) in experimental gliosis","volume":"659","author":"Rosenstein","year":"1994","journal-title":"Brain Res."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1046\/j.1471-4159.2004.02398.x","article-title":"Endothelin-1 stimulates the translocation and upregulation of both glucose transporter and hexokinase in astrocytes: relationship with gap junctional communication","volume":"89","author":"S\u00e1nchez-Alvarez","year":"2004","journal-title":"J. Neurochem."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1016\/j.brainres.2005.01.079","article-title":"The increase in gap junctional communication decreases the rate of glucose uptake in C6 glioma cells by releasing hexokinase from mitochondria","volume":"1039","author":"S\u00e1nchez-Alvarez","year":"2005","journal-title":"Brain Res."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"1766","DOI":"10.1038\/sj.jcbfm.9600521","article-title":"Supply and demand in cerebral energy metabolism: the role of nutrient transporters","volume":"27","author":"Simpson","year":"2007","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/j.neuint.2015.07.016","article-title":"Astrocytes from adult Wistar rats aged in vitro show changes in glial functions","volume":"90","author":"Souza","year":"2015","journal-title":"Neurochem. Int."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"1049","DOI":"10.1111\/j.1471-4159.2006.04088.x","article-title":"Glucose metabolism and proliferation in glia: role of astrocytic gap junctions","volume":"99","author":"Tabernero","year":"2006","journal-title":"J. Neurochem."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"10010","DOI":"10.1038\/s41598-019-46232-6","article-title":"The astrocyte transcriptome in EAE optic neuritis shows complement activation and reveals a sex difference in astrocytic C3 expression","volume":"9","author":"Tassoni","year":"2019","journal-title":"Sci. Rep."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"1147","DOI":"10.1210\/en.2017-00863","article-title":"cGMP\/PKG-I pathway\u2013mediated GLUT1\/4 regulation by NO in female rat granulosa cells","volume":"159","author":"Tian","year":"2017","journal-title":"Endocrinology"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1002\/(sici)1098-1136(199709)21:1<2::aid-glia2>3.0.co;2-c","article-title":"Glucose transporter proteins in brain: delivery of glucose to neurons and glia","volume":"21","author":"Vannucci","year":"1997","journal-title":"Glia"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"2521","DOI":"10.1210\/endo.138.6.5217","article-title":"Cyclic adenosine 3\u2032,5\u2032-monophosphate regulates GLUT4 and GLUT1 glucose transporter expression and stimulates transcriptional activity of the GLUT1 promoter in muscle cells","volume":"138","author":"Vinals","year":"1997","journal-title":"Endocrinology"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"452","DOI":"10.3389\/fcell.2020.00452","article-title":"The neurovascular unit in glaucomatous neurodegeneration","volume":"8","author":"Wareham","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/j.nbd.2018.09.002","article-title":"Increased bioavailability of cyclic guanylate monophosphate prevents retinal ganglion cell degeneration","volume":"121","author":"Wareham","year":"2018","journal-title":"Neurobiol. Dis."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1186\/s13024-022-00524-0","article-title":"Solving neurodegeneration: common mechanisms and strategies for new treatments","volume":"17","author":"Wareham","year":"2022","journal-title":"Mol. Neurodegener."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1038\/nn.3966","article-title":"GLUT1 reductions exacerbate Alzheimer\u2019s disease vasculo-neuronal dysfunction and degeneration","volume":"18","author":"Winkler","year":"2015","journal-title":"Nat. Neurosci."}],"container-title":["Frontiers in Cellular Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncel.2026.1870679\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T23:10:15Z","timestamp":1782947415000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncel.2026.1870679\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,2]]},"references-count":44,"alternative-id":["10.3389\/fncel.2026.1870679"],"URL":"https:\/\/doi.org\/10.3389\/fncel.2026.1870679","relation":{},"ISSN":["1662-5102"],"issn-type":[{"value":"1662-5102","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,2]]},"article-number":"1870679"}}