{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T14:15:09Z","timestamp":1793196909534,"version":"4.5.0"},"reference-count":18,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:00:00Z","timestamp":1785369600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100008485","name":"Swiss Academy of Medical Sciences","doi-asserted-by":"publisher","award":["MD-PhD 06\/2025"],"award-info":[{"award-number":["MD-PhD 06\/2025"]}],"id":[{"id":"10.13039\/501100008485","id-type":"DOI","asserted-by":"publisher"}]},{"award":["MD-PhD 06\/2025"],"award-info":[{"award-number":["MD-PhD 06\/2025"]}],"id":[{"id":"https:\/\/ror.org\/011cav305","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sci.","Brain Sciences"],"abstract":"<jats:p>Background\/Objectives: Brain arteriovenous malformations (bAVMs) are complex cerebrovascular lesions that carry a substantial risk of intracranial hemorrhage, yet the biological mechanisms underlying vascular remodeling remain incompletely understood. As increasing evidence suggests that inflammatory processes contribute to vascular remodeling and bAVM progression, this study aimed to characterize the cellular composition of the immune microenvironment in human bAVMs at single-cell resolution and to identify immune cell populations associated with transcriptional programs related to angiogenesis and extracellular matrix remodeling. Methods: Publicly accessible single-cell RNA sequencing data from five human bAVM samples and five control brain specimens were analyzed. After quality control and data integration, immune cell types were annotated based on canonical marker gene expression. To assess biological processes relevant to vascular remodeling, the expression of predefined gene sets associated with angiogenesis and extracellular matrix remodeling, derived from the Molecular Signatures Database (MSigDB), was quantified across cell populations using rank-based gene set scoring (UCell). Differences between bAVM and control samples were evaluated at the sample level using the Wilcoxon rank-sum test. For each immune cell type, mean UCell scores were calculated per biological sample and compared between groups. To account for multiple comparisons across cell types, p-values were adjusted using the Benjamini\u2013Hochberg procedure. Results: After quality control, 46,360 immune cells were analyzed. Compared with control tissue, bAVMs showed numerically higher proportions of lymphoid (activated T cells and CD8 T cells) and myeloid populations (M1-like macrophages, monocytes, and dendritic cells). Angiogenesis-related transcriptional activity was highest in myeloid cells and significantly increased in bAVMs, particularly in M1-like macrophages (UCell score 0.22 vs. 0.13), dendritic cells (0.16 vs. 0.10) and monocytes (0.20 vs. 0.15), whereas proliferating CD8 T cells showed a lower score (0.04 vs. 0.05; adjusted p = 0.040 for all four). Extracellular matrix-related programs showed a similar but weaker and non-significant pattern in myeloid populations (e.g., monocytes, dendritic cells, microglia-like cells; adjusted p = 0.09). Conclusions: Our findings identify myeloid cells, particularly M1-like macrophages, monocytes and dendritic cells, as important immune populations associated with angiogenesis in bAVMs. These findings highlight a potential role of immune-driven vascular remodeling in the pathophysiology of bAVMs.<\/jats:p>","DOI":"10.3390\/brainsci16080811","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T13:55:11Z","timestamp":1785419711000},"page":"811","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Single-Cell Analysis of Brain Arteriovenous Malformations Reveals Pro-Angiogenic Myeloid Programs"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9272-3115","authenticated-orcid":false,"given":"Benjamin","family":"Beyersdorf","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Clinical Neuroscience Centre, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1514-1442","authenticated-orcid":false,"given":"Stefanos","family":"Voglis","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Clinical Neuroscience Centre, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland"},{"name":"Department of Neurosurgery, University Hospital Frankfurt, 60590 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6805-5150","authenticated-orcid":false,"given":"Zsolt","family":"Kulcsar","sequence":"additional","affiliation":[{"name":"Department of Neuroradiology, Clinical Neuroscience Centre, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4639-4474","authenticated-orcid":false,"given":"Luca","family":"Regli","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Clinical Neuroscience Centre, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2185-4526","authenticated-orcid":false,"given":"Menno R.","family":"Germans","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Clinical Neuroscience Centre, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"15008","DOI":"10.1038\/nrdp.2015.8","article-title":"Brain Arteriovenous Malformations","volume":"1","author":"Lawton","year":"2015","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"fcag039","DOI":"10.1093\/braincomms\/fcag039","article-title":"Anatomical Phenotyping and Staging of Brain Arteriovenous Malformations","volume":"8","author":"Beyersdorf","year":"2026","journal-title":"Brain Commun."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1212\/WNL.0000000000000688","article-title":"Untreated Brain Arteriovenous Malformation: Patient-Level Meta-Analysis of Hemorrhage Predictors","volume":"83","author":"Kim","year":"2014","journal-title":"Neurology"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Chen, Y., Zhu, W., Bollen, A.W., Lawton, M.T., Barbaro, N.M., Dowd, C.F., Hashimoto, T., Yang, G.-Y., and Young, W.L. (2008). Evidence of Inflammatory Cell Involvement in Brain Arteriovenous Malformations. Neurosurgery, 62.","DOI":"10.1227\/01.neu.0000333306.64683.b5"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3613","DOI":"10.1161\/STROKEAHA.113.002390","article-title":"Review of Cerebral Aneurysm Formation, Growth, and Rupture","volume":"44","author":"Chalouhi","year":"2013","journal-title":"Stroke"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2129","DOI":"10.1016\/j.jacc.2009.09.009","article-title":"Leducq Transatlantic Network on Atherothrombosis Inflammation in Atherosclerosis: From Pathophysiology to Practice","volume":"54","author":"Libby","year":"2009","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Rodemerk, J., Engel, A., Horstmann, J.L.H., Rauschenbach, L., Darkwah Oppong, M., Santos, A.N., Junker, A., Deuschl, C., Forsting, M., and Zhu, Y. (2025). Inflammation in Cerebral Cavernous Malformations: Differences between Malformation Related Epilepsy vs. Symptomatic Hemorrhage. Cells, 14.","DOI":"10.3390\/cells14191510"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1038\/35025220","article-title":"Angiogenesis in Cancer and Other Diseases","volume":"407","author":"Carmeliet","year":"2000","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.immuni.2016.02.015","article-title":"Macrophages in Tissue Repair, Regeneration, and Fibrosis","volume":"44","author":"Wynn","year":"2016","journal-title":"Immunity"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"52","DOI":"10.17554\/j.issn.2409-3548.2015.01.12","article-title":"The Role of Macrophage in the Pathogenesis of Brain Arteriovenous Malformation: Ma L et al. Role of Macrophage in Brain AVM","volume":"1","author":"Ma","year":"2015","journal-title":"Int. J. Hematol. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1007\/s10456-016-9519-4","article-title":"Persistent Infiltration and Pro-Inflammatory Differentiation of Monocytes Cause Unresolved Inflammation in Brain Arteriovenous Malformation","volume":"19","author":"Zhang","year":"2016","journal-title":"Angiogenesis"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1038\/s41586-024-07493-y","article-title":"Single-Cell Atlas of the Human Brain Vasculature across Development, Adulthood and Disease","volume":"632","author":"Ghobrial","year":"2024","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"eabi7377","DOI":"10.1126\/science.abi7377","article-title":"A Single-Cell Atlas of the Normal and Malformed Human Brain Vasculature","volume":"375","author":"Winkler","year":"2022","journal-title":"Science"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Wagner, J., Rapsomaniki, M.A., Chevrier, S., Anzeneder, T., Langwieder, C., Dykgers, A., Rees, M., Ramaswamy, A., Muenst, S., and Soysal, S.D. (2019). A Single-Cell Atlas of the Tumor and Immune Ecosystem of Human Breast Cancer. Cell, 177.","DOI":"10.1016\/j.cell.2019.03.005"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1038\/s43018-021-00301-w","article-title":"Three-Dimensional Imaging Mass Cytometry for Highly Multiplexed Molecular and Cellular Mapping of Tissues and the Tumor Microenvironment","volume":"3","author":"Kuett","year":"2022","journal-title":"Nat. Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1016\/j.cell.2018.05.060","article-title":"Single-Cell Map of Diverse Immune Phenotypes in the Breast Tumor Microenvironment","volume":"174","author":"Azizi","year":"2018","journal-title":"Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1093\/bioinformatics\/btr260","article-title":"Molecular Signatures Database (MSigDB) 3.0","volume":"27","author":"Liberzon","year":"2011","journal-title":"Bioinformatics"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3796","DOI":"10.1016\/j.csbj.2021.06.043","article-title":"UCell: Robust and Scalable Single-Cell Gene Signature Scoring","volume":"19","author":"Andreatta","year":"2021","journal-title":"Comput. Struct. Biotechnol. J."}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/16\/8\/811\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:05:07Z","timestamp":1785420307000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/16\/8\/811"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,30]]},"references-count":18,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["brainsci16080811"],"URL":"https:\/\/doi.org\/10.3390\/brainsci16080811","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,30]]}}}