Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article Angiogenesis Development

Developmental vascular malformations in EPAS1 gain-of-function syndrome

  • Text
  • PDF
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

×

Figure 2

Extrinsic cervical spine venous malformations in HIF-2α gain-of-function syndrome patients.

Options: View larger image (or click on image) Download as PowerPoint
Extrinsic cervical spine venous malformations in HIF-2α gain-of-function...
Representative images are shown. (A) Axial CT of the neck with contrast of patient 1 shows cervical dysraphism at the level of C2 (left) due to a subfascial cavernous malformation of the upper neck (arrow). The malformation is continuous with the epidural veins (double-lined arrow) and large veins of the external spinal system (arrowhead). At the level of C3–4 (middle), the malformation (arrow) drains to a persistent segmental vein (arrowheads) of the spinal column bilaterally. These surround the vertebral artery (double-lined arrow). Large veins are seen throughout the soft tissues. Sagittal view of the left side of the same CT of the neck (right) showing the corresponding axial plane (green line). The posterior condylar emissary vein (arrow) is also seen draining to the malformation. (B) Posterior coronal view of the volumetric reconstruction of CT of the neck with contrast of patient 1 highlighting contrast and bone and excluding soft tissue demonstrates the veins (blue; arrowheads) entering and within the cavernous malformation (arrow) lined by persistent mesenchyme (red outline) extending from beneath the skull base down the length of the cervical spine. (C) Sagittal T1-weighted postcontrast MRI of the head demonstrates large sinusoidal veins (arrows) throughout the left lateral aspect of the neck of patient 2. (D) Coronal CT of the neck with contrast of patient 1 shows a venous malformation draining to the left jugular and subclavian veins (arrow).

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts