{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T13:33:38Z","timestamp":1793799218108,"version":"4.6.1"},"reference-count":39,"publisher":"SAGE Publications","issue":"11","license":[{"start":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T00:00:00Z","timestamp":1784678400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T00:00:00Z","timestamp":1784678400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"DOI":"10.13039\/501100001775","name":"university of technology sydney","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001775","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009287","name":"nsw health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100009287","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001775","name":"University of Technology Sydney","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001775","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001773","name":"university of new south wales","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001773","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"national natural science foundation of china","doi-asserted-by":"publisher","award":["82274233"],"award-info":[{"award-number":["82274233"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["J Cereb Blood Flow Metab"],"published-print":{"date-parts":[[2026,11]]},"abstract":"<jats:p>\n                    Cerebral cavernous malformations (CCMs) are common brain hemangioma that can occur sporadically or be inherited. CCM is one of the major causes of hemorrhagic stroke and neurological deficits in children. There are no pharmacological treatments for CCM. Clinical observations suggest that estrogen may have important roles in CCM, however, it has not been investigated. Hence, we investigated the role of estrogen and its nuclear receptors estrogen receptor-\u03b1 (\n                    <jats:italic toggle=\"yes\">Esr1<\/jats:italic>\n                    ) in experimental CCM. To determine the role of endothelial ESR1 in CCM, we crossed homozygous endothelial\n                    <jats:italic toggle=\"yes\">Esr1<\/jats:italic>\n                    (\n                    <jats:italic toggle=\"yes\">\n                      Esr1\n                      <jats:sup>fl\/fl<\/jats:sup>\n                    <\/jats:italic>\n                    ) mice into\n                    <jats:italic toggle=\"yes\">\n                      Ccm1\n                      <jats:sup>iECKO<\/jats:sup>\n                    <\/jats:italic>\n                    mice. Micro-computed tomography (micro-CT) imaging was used to analyze CCM burden. To determine the therapeutic potential of estrogen, we treated\n                    <jats:italic toggle=\"yes\">\n                      Ccm1\n                      <jats:sup>iECKO<\/jats:sup>\n                    <\/jats:italic>\n                    mice with\n                    <jats:italic toggle=\"yes\">estradiol (E2, a<\/jats:italic>\n                    clinically approved estrogen). Gene and protein expressions were assessed in human umbilical vein endothelial cells (HUVECs). Homozygous deletion of endothelial\n                    <jats:italic toggle=\"yes\">Esr1<\/jats:italic>\n                    in\n                    <jats:italic toggle=\"yes\">\n                      Ccm1\n                      <jats:sup>iECKO<\/jats:sup>\n                    <\/jats:italic>\n                    mice significantly increased CCM lesion volume compared to littermate controls. KLF2\/4 and downstream expressions in HUVECs were further increased by ESR1 depletion. This correlated with increased lesion burden in\n                    <jats:italic toggle=\"yes\">\n                      Ccm1\n                      <jats:sup>iECKO<\/jats:sup>\n                    <\/jats:italic>\n                    <jats:italic toggle=\"yes\">\n                      Esr1\n                      <jats:sup>fl\/fl<\/jats:sup>\n                    <\/jats:italic>\n                    mice. Furthermore, we demonstrated E2 treatment in\n                    <jats:italic toggle=\"yes\">\n                      Ccm1\n                      <jats:sup>iECKO<\/jats:sup>\n                    <\/jats:italic>\n                    mice prevented CCM pathogenesis by normalizing KLF2\/4 and downstream expressions. Our study demonstrates ESR1 as a novel targeted therapeutic option for CCM.\n                  <\/jats:p>","DOI":"10.1177\/0271678x261468891","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T04:03:49Z","timestamp":1783397029000},"page":"3138-3148","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Endothelial estrogen receptor alpha (ESR1) regulates cerebral cavernous malformation pathogenesis via MEKK3\u2013KLF signaling pathway"],"prefix":"10.1177","volume":"46","author":[{"given":"Hamidreza","family":"Sadegh","sequence":"first","affiliation":[{"name":"Faculty of Science, School of Life Sciences, Centre for Inflammation, Centenary Institute and University of Technology Sydney (UTS), Sydney NSW, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liwenyu","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Medicine, Nanjing University of Chinese Medicine, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suyun","family":"Yu","sequence":"additional","affiliation":[{"name":"School of Medicine, Nanjing University of Chinese Medicine, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sobia","family":"Idrees","sequence":"additional","affiliation":[{"name":"Faculty of Science, School of Life Sciences, Centre for Inflammation, Centenary Institute and University of Technology Sydney (UTS), Sydney NSW, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Foley","sequence":"additional","affiliation":[{"name":"Sydney Microscopy &amp; Microanalysis, The University of Sydney, Camperdown, NSW, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keshav Raj","family":"Paudel","sequence":"additional","affiliation":[{"name":"Faculty of Science, School of Life Sciences, Centre for Inflammation, Centenary Institute and University of Technology Sydney (UTS), Sydney NSW, Australia"},{"name":"NICM Health Research Institute, Western Sydney University, Westmead, NSW, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Li","sequence":"additional","affiliation":[{"name":"Curtin Medical School, Curtin Medical Research Institute, Curtin University, Bentley, WA, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Zhao","sequence":"additional","affiliation":[{"name":"School of Medicine, Nanjing University of Chinese Medicine, Nanjing, China"},{"name":"Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0135-8632","authenticated-orcid":false,"given":"Jaesung P","family":"Choi","sequence":"additional","affiliation":[{"name":"Faculty of Science, School of Life Sciences, Centre for Inflammation, Centenary Institute and University of Technology Sydney (UTS), Sydney NSW, Australia"},{"name":"School of Biomedical Sciences, UNSW Sydney, Kensington, NSW, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,7,22]]},"reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa070972"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2013.02.004"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI44393"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1097\/00006123-200006000-00027"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aau0731"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2018.3634"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/4.3.453"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/7.12.1851"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddi256"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.1918"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI39679"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature17178"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2014.12.009"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.120.031523"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20200140"},{"key":"e_1_3_3_17_2","article-title":"Micro-CT imaging reveals Mekk3 heterozygosity prevents cerebral cavernous malformations in Ccm2-deficient mice","volume":"11","author":"Choi JP","year":"2016","unstructured":"Choi JP, Foley M, Zhou Z, et al. 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