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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 5

Failure of early vascular regression in EPAS1 gain-of-function mouse model leads to persistent venous anomalies and malformations.

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Failure of early vascular regression in EPAS1 gain-of-function mouse mod...
(A) Representative images of intravital 2-photon microscopy of leptomeningeal and parenchymal vessels through a thinned skull window following retro-orbital i.v. injection for tomato lectin DyLight 488 and Evans blue demonstrated increased density and tortuosity of pial arterioles and venules and parenchymal capillaries in the mutant compared with the littermate control. Scale bar: 50 μm. Data represent the mean ± SEM. Quantification of n = 6 (3 mutant, 3 control) is shown; 2-tailed t test, P value equals 0.014. *P < 0.05. (B) H&E staining of the mouse model brain shows a developmentally large vein of Galen (arrow), large leptomeningeal and parenchymal veins (arrowheads), and cavernous angiomas arising directly from these veins (double-lined arrow); controls are shown. Large veins throughout enlarged Virchow-Robin spaces are also seen in the mutant. Scale bars: 200 μm (top left and top middle), 400 μm (top right); for the CTRL: 200 μm (bottom left and bottom middle), 400 μm (bottom right). (C) Representative images of isolectin B4 staining of the mouse model superficial plexus of the retina at postnatal time points 7, 14, and 21 days (P7–P21), during which the retinal vasculature of the mouse completes development, demonstrates that the plexiform network of veins fail to regress in the mutant compared with the control. This persists in the dura as evaluated at 5 months old.

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