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Developmental vascular malformations in EPAS1 gain-of-function syndrome
Jared S. Rosenblum, … , Zhengping Zhuang, Karel Pacak
Jared S. Rosenblum, … , Zhengping Zhuang, Karel Pacak
Published January 26, 2021
Citation Information: JCI Insight. 2021;6(5):e144368. https://doi.org/10.1172/jci.insight.144368.
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Research Article Angiogenesis Development

Developmental vascular malformations in EPAS1 gain-of-function syndrome

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Abstract

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.

Authors

Jared S. Rosenblum, Herui Wang, Pauline M. Dmitriev, Anthony J. Cappadona, Panagiotis Mastorakos, Chen Xu, Abhishek Jha, Nancy Edwards, Danielle R. Donahue, Jeeva Munasinghe, Matthew A. Nazari, Russell H. Knutsen, Bruce R. Rosenblum, James G. Smirniotopoulos, Alberto Pappo, Robert F. Spetzler, Alexander Vortmeyer, Mark R. Gilbert, Dorian B. McGavern, Emily Chew, Beth A. Kozel, John D. Heiss, Zhengping Zhuang, Karel Pacak

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Figure 4

Venous anomalies and malformations in HIF-2α gain-of-function syndrome mouse model.

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Venous anomalies and malformations in HIF-2α gain-of-function syndrome m...
Representative images are shown. (A) Axial view 3D volumetric reconstruction of micro-CT of the polymer-casted mouse model (MUT) shows a prominent confluence of sinuses (arrow) compared with control (CTRL) and a vascular malformation arising from the junction of the superior sagittal sinus and rostral rhinal sinus (double-lined arrow). Prominent occipital emissary veins (arrowheads) are seen in the mutant. (B) Sagittal ex vivo T1-weighted MRI (top) shows an enlarged vein of Galen (arrowhead) arising from a large superior sagittal sinus (arrow) in the mutant; the coronal slice (middle) corresponds to the green line in the sagittal view and shows prominent vessels throughout the parenchyma. Midsagittal section of another mutant (bottom) shows a lesion in the olfactory bulb (arrow) arising from large anomalous veins (arrowhead). The normal caliber of the vein of Galen (arrow) is shown in the control. (C) Midsagittal 3D volumetric reconstruction of micro-CT (left) of the mutant from B (bottom) shows the lesion in the olfactory bulb (arrow) and the draining vessel (arrowhead). Coronal histologic section (right) of the same sample at original magnification ×10 stained with H&E shows a subarachnoid cerebrospinal fluid (CSF) cavity (arrow) between the olfactory bulbs surrounding the anterior portion of the falx, which has large veins in it (arrowhead), most likely consistent with CSF-venous fistula, as supported by the retrograde perfusion of polymer into this space seen on micro-CT. (D) Gross photograph of a suspected cavernous malformation (arrow) arising from a branch of the inferior vena cava (arrowhead) in the mutant. The right auricle (not visualized) is ligated. H, heart; L, lung. H&E-stained histologic section of the specimen reveals blood-filled dilated vascular channels associated with organizing thrombotic material and reactive inflammation consistent with cavernous angioma. Scale bar: 60 μm.

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