{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T06:19:48Z","timestamp":1788848388304,"version":"build-2803163510"},"reference-count":41,"publisher":"American Society for Clinical Investigation","issue":"5","license":[{"start":{"date-parts":[[2021,3,8]],"date-time":"2021-03-08T00:00:00Z","timestamp":1615161600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["Intramural Program of NCI"],"award-info":[{"award-number":["Intramural Program of NCI"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["Intramural program of NINDS"],"award-info":[{"award-number":["Intramural program of NINDS"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["Intramural program of NICHD"],"award-info":[{"award-number":["Intramural program of NICHD"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["Intramural program of NHLBI"],"award-info":[{"award-number":["Intramural program of NHLBI"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100016778","name":"Paradifference Foundation","doi-asserted-by":"crossref","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100016778","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,3,8]]},"abstract":"<jats:p>\n                    Mutations in\n                    <jats:italic>EPAS1<\/jats:italic>\n                    , encoding hypoxia-inducible factor-2\u03b1 (HIF-2\u03b1), were previously identified in a syndrome of multiple paragangliomas, somatostatinoma, and polycythemia. HIF-2\u03b1, when dimerized with HIF-1\u03b2, acts as an angiogenic transcription factor. Patients referred to the NIH for new, recurrent, and\/or metastatic paraganglioma or pheochromocytoma were confirmed for\n                    <jats:italic>EPAS1<\/jats:italic>\n                    gain-of-function mutation; imaging was evaluated for vascular malformations. We evaluated the\n                    <jats:italic>Epas1<\/jats:italic>\n                    <jats:sup>A529V<\/jats:sup>\n                    transgenic syndrome mouse model, corresponding to the mutation initially detected in the patients (\n                    <jats:italic>EPAS1<\/jats:italic>\n                    <jats:sup>A530V<\/jats:sup>\n                    ), for vascular malformations via intravital 2-photon microscopy of meningeal vessels, terminal vascular perfusion with Microfil silicate polymer and subsequent intact ex vivo 14T MRI and micro-CT, and histologic sectioning and staining of the brain and identified pathologies. Further, we evaluated retinas from corresponding developmental time points (P7, P14, and P21) and the adult dura via immunofluorescent labeling of vessels and confocal imaging. We identified a spectrum of vascular malformations in all 9 syndromic patients and in all our tested mutant mice. Patient vessels had higher variant allele frequency than adjacent normal tissue. Veins of the murine retina and intracranial dura failed to regress normally at the expected developmental time points. These findings add vascular malformation as a new clinical feature of\n                    <jats:italic>EPAS1<\/jats:italic>\n                    gain-of-function syndrome.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.144368","type":"journal-article","created":{"date-parts":[[2021,1,26]],"date-time":"2021-01-26T12:40:52Z","timestamp":1611664852000},"source":"Crossref","is-referenced-by-count":25,"title":["Developmental vascular malformations in EPAS1 gain-of-function syndrome"],"prefix":"10.1172","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5941-9082","authenticated-orcid":true,"given":"Jared S.","family":"Rosenblum","sequence":"first","affiliation":[{"name":"Neuro-Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland, 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USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0505-6938","authenticated-orcid":true,"given":"Panagiotis","family":"Mastorakos","sequence":"additional","affiliation":[{"name":"Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland, USA."},{"name":"Viral Immunology and Intravital Imaging Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Xu","sequence":"additional","affiliation":[{"name":"Neuro-Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1489-2471","authenticated-orcid":true,"given":"Abhishek","family":"Jha","sequence":"additional","affiliation":[{"name":"Section on Medical Neuroendocrinology,  Eunice Kennedy Shriver  National 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