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Here, we established rat models of high intraocular pressure (HIOP) and lipopolysaccharide\u2010induced ocular inflammation (LPS), and performed single\u2010cell RNA sequencing (scRNA\u2010seq) of ONH\u2010centered tissues to characterize the cellular and molecular characteristics of NVU and its main cell components. Distinct alterations in the cellular composition and intercellular communication of the ONH\u2010NVU were observed among Ctrl, HIOP and LPS conditions. Astrocytes showed a prominent increase of relative proportion in the HIOP group, whereas microglia were preferentially expanded under LPS stimulation. Astrocytes, microglia and endothelial cells showed a firm interaction via cell\u2013cell communication analysis, in which the interactions within astrocytes and endothelial cells were the highest. Reclustering of main NVU cell types were further identified distinct subpopulations, including\n                    <jats:italic>Dcn<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>+<\/jats:italic>\n                    <\/jats:sup>\n                    <jats:italic>Myoc<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>+<\/jats:italic>\n                    <\/jats:sup>\n                    astrocytes,\n                    <jats:italic>S100a8<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>+<\/jats:italic>\n                    <\/jats:sup>\n                    <jats:italic>S100a9<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>+<\/jats:italic>\n                    <\/jats:sup>\n                    microglia and\n                    <jats:italic>Nebl<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>+<\/jats:italic>\n                    <\/jats:sup>\n                    <jats:italic>Cytl1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>+<\/jats:italic>\n                    <\/jats:sup>\n                    endothelial cells with prominent heterogeneity features, and their cellular interactions exhibited a prominent integrin\u2010collagen network in orchestrating ECM restructuring under HIOP conditions. Additional histomorphological analysis further verified the early collapse of ONH astrocytic network and RGC degeneration. Therefore, these findings reveal the distinct ONH\u2010NVU heterogeneity under HIOP condition, the astrocyte\u2010mediated ECM remodeling may serve as a key early mechanobiological event for subsequent ONH cupping and glaucomatous neurodegeneration.\n                  <\/jats:p>","DOI":"10.1096\/fj.202602523rr","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T09:16:17Z","timestamp":1790846177000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Heterogeneity of the Neurovascular Unit in the Optic Nerve Head During Glaucomatous Neurodegeneration Based on Single\u2010Cell\n                    <scp>RNA<\/scp>\n                    Sequencing"],"prefix":"10.1096","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7185-4252","authenticated-orcid":false,"given":"Ying","family":"Cheng","sequence":"first","affiliation":[{"name":"Department of Ophthalmology The First Affiliated Hospital of Xi'an Jiaotong University  Xi'an Shaanxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shen","family":"Wu","sequence":"additional","affiliation":[{"name":"Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital Capital Medical University, Beijing Key Laboratory of Intelligent Diagnosis Technology and Equipment for Optic Nerve\u2010Related Eye Diseases  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danting","family":"Lin","sequence":"additional","affiliation":[{"name":"Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital Capital Medical University, Beijing Key Laboratory of Intelligent Diagnosis Technology and Equipment for Optic Nerve\u2010Related Eye Diseases  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiqi","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology The 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Science  Zhengzhou Henan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingxue","family":"Zhang","sequence":"additional","affiliation":[{"name":"Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital Capital Medical University, Beijing Key Laboratory of Intelligent Diagnosis Technology and Equipment for Optic Nerve\u2010Related Eye Diseases  Beijing China"},{"name":"Henan Academy of Innovations in Medical Science  Zhengzhou Henan 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