{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T14:47:57Z","timestamp":1783349277994,"version":"3.54.6"},"reference-count":41,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2025,8,15]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>Cerebrovascular malformations are a pivotal cause of hemorrhage and neurological disability, orchestrated largely by aberrant vascular homeostasis. However, a malformed angiogenic regulation pattern remains elusive.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>\n              Single-cell transcriptome analysis uncovered the endothelial features of human cerebral cavernous malformations and brain arteriovenous malformations, 2 typical cerebrovascular malformation diseases. Endothelial AR (androgen receptor, a steroid receptor in the nuclear receptor superfamily) overexpression was conducted to investigate its involvement in tip cell formation. ARD-2585, an AR degrader, was applied to mouse models of cerebral cavernous malformations (endothelial-specific\n              <jats:italic toggle=\"yes\">Pdcd10<\/jats:italic>\n              knockout mice) and brain arteriovenous malformations (endothelial-specific\n              <jats:italic toggle=\"yes\">Kras<\/jats:italic>\n              <jats:sup>\n                <jats:italic toggle=\"yes\">G12D<\/jats:italic>\n              <\/jats:sup>\n              mutant [\n              <jats:italic toggle=\"yes\">Kras<\/jats:italic>\n              <jats:sup>\n                <jats:italic toggle=\"yes\">G12D<\/jats:italic>\n              <\/jats:sup>\n              ] mice) to evaluate its vascular rescue potential.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              We profiled single-cell transcriptomes of 13 human cerebrovascular malformation samples (10 cerebral cavernous malformations and 3 brain arteriovenous malformations) and 13 control brain samples, identifying a crucial pathological tip cell population in lesions. Integrative bioinformatics revealed a systemic endothelial regulatory network, with AR as a key regulator of this aberrant state. AR expression was elevated in endothelial cells from both human cerebrovascular malformations and\n              <jats:italic toggle=\"yes\">Pdcd10<\/jats:italic>\n              knockout\/\n              <jats:italic toggle=\"yes\">Kras<\/jats:italic>\n              <jats:sup>\n                <jats:italic toggle=\"yes\">G12D<\/jats:italic>\n              <\/jats:sup>\n              mice, correlating with suppressed Dll4 (delta-like canonical Notch ligand 4)-Notch signaling. AR overexpression augmented endothelial tube formation, filopodia extension, and polarization in vitro and fostered sex-independent vascular sprouting in vivo. High levels of AR facilitated proangiogenic gene transcription by recruiting coactivators EP300 (EP300 lysine acetyltransferase)\/CBP (CREB binding lysine acetyltransferase), augmenting histone H3 lysine 18\/histone H3 lysine 27 acetylation, and boosting chromatin accessibility, potentially independent of androgen. Notably, ARD-2585 treatment effectively normalized vascular anomalies and alleviated cerebral hemorrhage in\n              <jats:italic toggle=\"yes\">Pdcd10<\/jats:italic>\n              knockout and\n              <jats:italic toggle=\"yes\">Kras<\/jats:italic>\n              <jats:sup>\n                <jats:italic toggle=\"yes\">G12D<\/jats:italic>\n              <\/jats:sup>\n              mice.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>We delineated a novel androgen-independent AR-mediated endothelial sprouting pattern in malformed cerebrovasculature, highlighting a promising foundation for developing interventions targeting tip cells in angiogenic diseases.<\/jats:p>\n          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Academy of Medical Sciences and Peking Union Medical College, Beijing (R.L., L.Y., M.X., X.X., Y.T., C.L., Y.Z., Y.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengchen","family":"Xu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing (R.L., L.Y., M.X., X.X., Y.T., C.L., Y.Z., Y.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Xiao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing (R.L., L.Y., M.X., X.X., Y.T., C.L., Y.Z., Y.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yushan","family":"Tang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing (R.L., L.Y., M.X., X.X., Y.T., C.L., Y.Z., Y.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Lv","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing (R.L., L.Y., M.X., X.X., Y.T., C.L., Y.Z., Y.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, 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