Developmental vascular malformations in EPAS1 gain-of-function syndrome.

Autor:	Rosenblum JS; Neuro-Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland, USA., Wang H; Neuro-Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland, USA., Dmitriev PM; Neuro-Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland, USA., Cappadona AJ; Neuro-Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland, USA., Mastorakos P; Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland, USA.; Viral Immunology and Intravital Imaging Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland, USA., Xu C; Neuro-Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland, USA., Jha A; Section on Medical Neuroendocrinology, Eunice Kennedy Shriver, National Institute of Child Health and Human Development, NIH, Bethesda, Maryland, USA., Edwards N; Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland, USA., Donahue DR; Mouse Imaging Facility, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland, USA., Munasinghe J; Mouse Imaging Facility, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland, USA., Nazari MA; Internal Medicine and Pediatrics, MedStar Georgetown University Hospital, Washington, DC, USA., Knutsen RH; Laboratory of Vascular and Matrix Genetics, National Heart Lung and Blood Institute, NIH, Bethesda, Maryland, USA., Rosenblum BR; Department of Neurosurgery, Riverview Medical Center, Red Bank, New Jersey, USA., Smirniotopoulos JG; Department of Radiology, School of Medicine and Health Sciences, George Washington University, Washington, DC, USA.; National Library of Medicine, Bethesda, Maryland, USA., Pappo A; Oncology Department, Developmental Biology and Solid Tumor Program, St. Jude Comprehensive Cancer Center, St. Jude Children's Research Hospital, Memphis, Tennessee, USA., Spetzler RF; Department of Neurosurgery, Barrow Neurological Institute, St. Joseph's Hospital, and Medical Center, Phoenix, Arizona, USA., Vortmeyer A; Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA., Gilbert MR; Neuro-Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland, USA., McGavern DB; Viral Immunology and Intravital Imaging Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland, USA., Chew E; Division of Epidemiology and Clinical Applications, National Eye Institute, NIH, Bethesda, Maryland, USA., Kozel BA; Laboratory of Vascular and Matrix Genetics, National Heart Lung and Blood Institute, NIH, Bethesda, Maryland, USA., Heiss JD; Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland, USA., Zhuang Z; Neuro-Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland, USA., Pacak K; Section on Medical Neuroendocrinology, Eunice Kennedy Shriver, National Institute of Child Health and Human Development, NIH, Bethesda, Maryland, USA.
Jazyk:	angličtina
Zdroj:	JCI insight [JCI Insight] 2021 Mar 08; Vol. 6 (5). Date of Electronic Publication: 2021 Mar 08.
DOI:	10.1172/jci.insight.144368
Abstrakt:	Mutations in EPAS1, encoding hypoxia-inducible factor-2α (HIF-2α), were previously identified in a syndrome of multiple paragangliomas, somatostatinoma, and polycythemia. HIF-2α, when dimerized with HIF-1β, acts as an angiogenic transcription factor. Patients referred to the NIH for new, recurrent, and/or metastatic paraganglioma or pheochromocytoma were confirmed for EPAS1 gain-of-function mutation; imaging was evaluated for vascular malformations. We evaluated the Epas1A529V transgenic syndrome mouse model, corresponding to the mutation initially detected in the patients (EPAS1A530V), 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 EPAS1 gain-of-function syndrome.
Databáze:	MEDLINE
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