{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T23:14:01Z","timestamp":1791155641818,"version":"4.1.0"},"reference-count":44,"publisher":"National Academy of Sciences","issue":"31","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2008,8,5]]},"abstract":"<jats:p>\n                    Brain arteriovenous malformations (BAVMs) can cause devastating stroke in young people and contribute to half of all hemorrhagic stroke in children. Unfortunately, the pathogenesis of BAVMs is unknown. In this article we show that activation of Notch signaling in the endothelium during brain development causes BAVM in mice. We turned on constitutively active Notch4 (\n                    <jats:italic>int3<\/jats:italic>\n                    ) expression in endothelial cells from birth by using the tetracycline-regulatable system. All mutants developed hallmarks of BAVMs, including cerebral arteriovenous shunting and vessel enlargement, by 3 weeks of age and died by 5 weeks of age. Twenty-five percent of the mutants showed signs of neurological dysfunction, including ataxia and seizure. Affected mice exhibited hemorrhage and neuronal cell death within the cerebral cortex and cerebellum. Strikingly,\n                    <jats:italic>int3<\/jats:italic>\n                    repression resolved ataxia and reversed the disease progression, demonstrating that\n                    <jats:italic>int3<\/jats:italic>\n                    is not only sufficient to induce, but also required to sustain the disease. We show that\n                    <jats:italic>int3<\/jats:italic>\n                    expression results in widespread enlargement of the microvasculature, which coincided with a reduction in capillary density, linking vessel enlargement to Notch's known function of inhibiting vessel sprouting. Our data suggest that the Notch pathway is a molecular regulator of BAVM pathogenesis in mice, and offer hope that their regression might be possible by targeting the causal molecular lesion.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0802743105","type":"journal-article","created":{"date-parts":[[2008,7,30]],"date-time":"2008-07-30T22:00:34Z","timestamp":1217455234000},"page":"10901-10906","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":134,"title":["Endothelial Notch4 signaling induces hallmarks of brain arteriovenous malformations in mice"],"prefix":"10.1073","volume":"105","author":[{"given":"Patrick A.","family":"Murphy","sequence":"first","affiliation":[{"name":"*Pacific Vascular Research Laboratory, Division of Vascular Surgery, Department of Surgery, and Department of Anatomy and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael T. Y.","family":"Lam","sequence":"additional","affiliation":[{"name":"*Pacific Vascular Research Laboratory, Division of Vascular Surgery, Department of Surgery, and Department of Anatomy and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoqing","family":"Wu","sequence":"additional","affiliation":[{"name":"*Pacific Vascular Research Laboratory, Division of Vascular Surgery, Department of Surgery, and Department of Anatomy and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyson N.","family":"Kim","sequence":"additional","affiliation":[{"name":"*Pacific Vascular Research Laboratory, Division of Vascular Surgery, Department of Surgery, and Department of Anatomy and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shant M.","family":"Vartanian","sequence":"additional","affiliation":[{"name":"*Pacific Vascular Research Laboratory, Division of Vascular Surgery, Department of Surgery, and Department of Anatomy and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew W.","family":"Bollen","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of California, San Francisco, CA 94143"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy R.","family":"Carlson","sequence":"additional","affiliation":[{"name":"*Pacific Vascular Research Laboratory, Division of Vascular Surgery, Department of Surgery, and Department of Anatomy and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong A.","family":"Wang","sequence":"additional","affiliation":[{"name":"*Pacific Vascular Research Laboratory, Division of Vascular Surgery, Department of Surgery, and Department of Anatomy and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2008,8,5]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMcp067192"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1097\/01.wco.0000200546.14668.78"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.3171\/jns.1996.85.1.0001"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1111\/1523-1747.ep12555569"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.12.3.207"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81436-1"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.01074"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0925-4773(01)00469-5"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrg888"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1239204"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0504391102"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.128.19.3675"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.091584598"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2005.03.009"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/6165"},{"key":"e_1_3_3_16_2","first-page":"35","volume-title":"Vascular Diseases","author":"Capron L","year":"1988","unstructured":"L Capron Vascular Diseases, ed PJ Vinken (Elsevier, New York), pp. 35\u201362 (1988)."},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.32.6.1430"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature05571"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1148\/radiology.182.2.1732966"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2006.12.028"},{"key":"e_1_3_3_21_2","first-page":"3","volume-title":"The Rat Nervous System","author":"Scremin OU","year":"1995","unstructured":"OU Scremin The Rat Nervous System, ed G Paxinos (Academic, San Diego), pp. 3\u201335 (1995)."},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2005.030833"},{"key":"e_1_3_3_23_2","first-page":"1016","article-title":"Angiographic and clinical characteristics of patients with cerebral arteriovenous malformations associated with hereditary hemorrhagic telangiectasia","volume":"21","author":"Matsubara S","year":"2000","unstructured":"S Matsubara, et al., Angiographic and clinical characteristics of patients with cerebral arteriovenous malformations associated with hereditary hemorrhagic telangiectasia. 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