TY - JOUR
T1 - Developmental vascular malformations in EPAS1 gain-of-function syndrome
AU - Rosenblum, Jared S.
AU - Wang, Herui
AU - Dmitriev, Pauline M.
AU - Cappadona, Anthony J.
AU - Mastorakos, Panagiotis
AU - Xu, Chen
AU - Jha, Abhishek
AU - Edwards, Nancy
AU - Donahue, Danielle R.
AU - Munasinghe, Jeeva
AU - Nazari, Matthew A.
AU - Knutsen, Russell H.
AU - Rosenblum, Bruce R.
AU - Smirniotopoulos, James G.
AU - Pappo, Alberto
AU - Spetzler, Robert F.
AU - Vortmeyer, Alexander
AU - Gilbert, Mark R.
AU - McGavern, Dorian B.
AU - Chew, Emily
AU - Kozel, Beth A.
AU - Heiss, John D.
AU - Zhuang, Zhengping
AU - Pacak, Karel
N1 - Publisher Copyright:
© 2021, Rosenblum et al.
PY - 2021/3/8
Y1 - 2021/3/8
N2 - 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.
AB - 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.
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U2 - 10.1172/jci.insight.144368
DO - 10.1172/jci.insight.144368
M3 - Article
C2 - 33497361
AN - SCOPUS:85102433901
SN - 2379-3708
VL - 6
JO - JCI Insight
JF - JCI Insight
IS - 5
M1 - e144368
ER -